P. Lagos | Universidad de la República (Uruguay) (original) (raw)

Papers by P. Lagos

Sleep Medicine, 2009

Conclusion: These results show that sleep loss can affect sexual motivation and might lead to imp... more Conclusion: These results show that sleep loss can affect sexual motivation and might lead to important clinical implications, including alterations in female physiology and reproductive abnormalities.

Peptides, 2013

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsib... more The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5 min, P<0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5 min, P<0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

European Neuropsychopharmacology, 1998

Quantitation of 2 h sessions after administration of the D preferring dopamine (DA) agonist prami... more Quantitation of 2 h sessions after administration of the D preferring dopamine (DA) agonist pramipexole (10-500 mg / kg) showed 3 dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 mg / kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 mg / kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 mg / kg dose during the second recording hour. The mixed D-and D 2 3 receptor antagonist YM-09151-2 (30-500 mg / kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500-1000 mg / kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 mg / kg dose of the DA agonist. Pramipexole (30-100 mg / kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 mg / kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 mg / kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D receptor could be involved in the pramipexole-3 induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D receptor.

Brazilian Journal of Medical and Biological Research, 2001

Sea anemones are a rich source of biologically active substances. In crayfish muscle fibers, Buno... more Sea anemones are a rich source of biologically active substances. In crayfish muscle fibers, Bunodosoma cangicum whole venom selectively blocks the I K(Ca) currents. In the present study, we report for the first time powerful hemolytic and neuroactive effects present in two different fractions obtained by gel-filtration chromatography from whole venom of B. cangicum. A cytolytic fraction (Bcg-2) with components of molecular mass ranging from 8 to 18 kDa elicited hemolysis of mouse erythrocytes with an EC 50 = 14 µg/ml and a maximum dose of 22 µg/ml. The effects of the neuroactive fraction, Bcg-3 (2 to 5 kDa), were studied on isolated crab nerves. This fraction prolonged the compound action potentials by increasing their duration and rise time in a dose-dependent manner. This effect was evident after the washout of the preparation, suggesting the existence of a reversible substance that was initially masking the effects of an irreversible one. In order to elucidate the target of Bcg-3 action, the fraction was applied to a tetraethylammonium-pretreated preparation. An additional increase in action potential duration was observed, suggesting a blockade of a different population of K + channels or of tetraethylammonium-insensitive channels. Also, tetrodotoxin could not block the action potentials in a Bcg-3-pretreated preparation, suggesting a possible interaction of Bcg-3 with Na + channels. The present data suggest that B. cangicum venom contains at least two bioactive fractions whose activity on cell membranes seems to differ from the I K(Ca) blockade described previously.

Brain Research, 2008

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized within... more Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized within the postero-lateral hypothalamus and zona incerta. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes such as energy homeostasis and sleep. In the present report, we examined the distribution of MCH immunoreactivity in the brainstem of the cat. In addition to MCH+ axons, we found MCH-immunoreactive cells that have not been previously described either in the midbrain raphe nuclei or in the periaqueductal and periventricular areas. These MCH+ cells constituted: 1. ependymal cells that lined the fourth ventricle and aqueduct, 2. ependymal cells with long basal processes that projected deeply into the subventricular (subaqueductal) parenchyma, and, 3. cells in subventricular regions and the midbrain raphe nuclei. The MCH+ cells in the midbrain raphe nuclei were closely related to neuronal processes of serotonergic neurons. Utilizing Neu-N and GFAP immunohistochemistry we determined that the preceding MCH+ cells were neither neurons nor astrocytes. However, we found that vimentin, an intermediate-filament protein that is used as a marker for tanycytes, was specifically co-localized with MCH in these cells. We conclude that MCH is present in tanycytes whose processes innervate the midbrain raphe nuclei and adjacent subependymal regions. Because tanycytes are specialized cells that transport substances from the cerebrospinal fluid (CSF) to neural parenchyma, we suggest that MCH is absorbed from the CSF by tanycytes and subsequently liberate to act upon neurons of brainstem nuclei.

Behavioural Brain Research, 2011

Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown... more Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown to have antidepressant-like profile in rats. However, the mechanisms by which the MCHergic system participates in the modulation of emotional states are still to be determined. In the present study we confirmed the presence of MCHergic fibers within the dorsal raphe nucleus (DRN), a serotonergic nucleus involved in the physiopathology of major depression. We also assessed the effects of the administration of MCH and anti-MCH antibody (immunoneutralization) into the DRN using the forced swim test in rats, an animal model to screen antidepressant drugs. We found that a low dose of MCH (50 ng) evoked a depressive-like behavior indicated by a significant increase in the immobility time as well as a decrease in climbing behavior. Furthermore, the depressive-like response was prevented by pretreatment with fluoxetine. Consistent with these results, the immunoneutralization of MCH produced an antidepressant-like effect. By means of the open field test we discarded that these effects were related to unspecific changes in motor activity. Our results suggest that the MCHergic neurons are involved in the regulation of emotional behaviors through the modulation of the serotonergic neuronal activity within the DRN. In addition, the present results are in agreement with previous reports showing that antagonism of the MCHergic system may be a novel therapeutic strategy for the treatment of depressive disorders.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2015

A study was carried out on the effects of unilateral microinjection of melanin-concentrating horm... more A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep-wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

Biological Psychiatry, 1997

Melanin-concentrating hormone (MCH)-containing neurons are localized in the lateral hypothalamus ... more Melanin-concentrating hormone (MCH)-containing neurons are localized in the lateral hypothalamus and incerto-hypothalamic areas, and project to several brain regions including the dorsal raphe nucleus (DRN). The MCHergic system has been involved in the regulation of emotional states and we have demonstrated that MCH microinjections into the rat DRN promote a depressive-like state. To understand the MCHergic transmission into the DRN, in the present study we characterized the distribution and density of the MCHergic fibers along the rostro-caudal axis of the rat DRN and their anatomical relationship with the 5-HT-and GABA-containing neurons. Additionally, a functional in vivo microdialysis study was carried out in order to evaluate the MCH effects on the 5-HT extracellular levels.

Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromo-dulator are lo... more Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromo-dulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons send dense projections to the dorsal raphe nucleus (DRN). Serotonergic neurons of the DRN are involved in the control of sleep and play a critical role in major depression. Previously, we demonstrated that microinjections of MCH into the DRN resulted in an increase in REM sleep and produce a depressive-like effect. In the present study we examined the mechanisms that mediate these effects by employing neuroanatomical and electrophysiological techniques. First, we determined that rhodamine-labeled MCH (R-MCH), when microinjected into the lateral ventricle, is internalized in serotonergic and non-serotonergic DRN neurons in rats and cats. These data strongly suggest that these neurons express MCHergic receptors. Second, in rats, we demonstrated that the microinjection of MCH into the lateral ventricle results in a significant decrease in the firing rate in 59% of the neurons recorded in the DRN; the juxtacellular administration of MCH reduced the discharge in 80% of these neurons. Some of the neurons affected by MCH were likely serotonergic on the basis of their electrophysiological and pharmacological properties. We conclude that MCH reduces the activity of serotonergic neurons of the DRN. These and previous data suggest that the MCHergic modulation of serotonergic activity within the DRN is involved in the regulation of REM sleep as well as in the pathophysiology of depressive disorders.

A study was carried out on the effects of unilateral microinjection of melanin-concentrating horm... more A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep–wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lat... more Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system and play a role in sleep regulation. With the hypothesis that the MCHergic system function would be modified by the time of the day as well as by disruptions of the sleep-wake cycle, we quantified in rats the concentration of MCH in the cerebrospinal fluid (CSF), the expression of the MCH precursor (Pmch) gene in the hypothalamus, and the expression of the MCH receptor 1 (Mchr1) gene in the frontal cortex and hippocampus. These analyses were performed during paradoxical sleep deprivation (by a modified multiple platform technique), paradoxical sleep rebound and chronic sleep restriction, both at the end of the active (dark) phase (lights were turned on at Zeitgeber time zero, ZT0) and during the inactive (light) phase (ZT8). We observed that in control condition (waking and sleep ad libitum), Mchr1 gene expression was larger at ZT8 (when sleep predominates) than at ZT0, both in frontal cortex and hippocampus. In addition, compared to control, disturbances of the sleep–wake cycle produced the following effects: paradoxical sleep deprivation for 96 and 120 h reduced the expression of Mchr1 gene in frontal cortex at ZT0. Sleep rebound that followed 96 h of paradoxical sleep deprivation increased the MCH concentration in the CSF also at ZT0. Twenty-one days of sleep restriction produced a significant increment in MCH CSF levels at ZT8. Finally, sleep disruptions unveiled day/night differences in MCH CSF levels and in Pmch gene expression that were not observed in control (undisturbed) conditions. In conclusion, the time of the day and sleep disruptions produced subtle modifications in the physiology of the MCHergic system.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of... more The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.

Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has be... more Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25–100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T 30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T 30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant. Behavioural Pharmacology 25:316–324

Resumen Intro duc ción: la de pre sión ma yor (DM) es una en fer me dad psi quiá tri ca fre cuen ... more Resumen Intro duc ción: la de pre sión ma yor (DM) es una en fer me dad psi quiá tri ca fre cuen te, con im por tan te mor bi li dad y una re la ción es-tre cha con el sui ci dio. Obje ti vo: ha cer una pues ta a pun to de los avan ces en el es tu dio de la neu ro bio lo gía de la DM, en fo cán do nos en el po si ble rol de la hor mo na con cen tra do ra de me la ni na (MCH) en esta pa to lo gía. Me to do lo gía: re vi sión de la bi blio gra fía con én fa sis en nues tros pro pios tra ba jos ori gi na les. Re sul ta dos: la MCH es un neu ro mo du la dor pep tí di co sin te ti za do por neu ro nas del hi po tá la mo. Las neu ro nas MCHér gi cas en-vían pro yec cio nes ha cia di ver sas re gio nes del sis te ma ner vio so cen tral, in clu yen do las áreas vin cu la das con la re gu la ción de la vi gi lia y del sue ño, así como a di ver sas es truc tu ras del sis te ma lím bi co que par ti ci pan en la re gu la ción del hu mor. Aun que nu me-ro sos es tu dios han re la cio na do el sis te ma MCHér gi co con el con trol de la ho meos ta sis ener gé ti ca, ha llaz gos re cien tes han per-mi ti do se ña lar un rol de este sis te ma en los me ca nis mos de ge ne ra ción del sue ño. A su vez, una con ver gen cia de da tos pro ve-nien tes de di ver sos es tu dios su gie re que la MCH es ta ría in vo lu cra da en la fi sio pa to lo gía de la DM. Nues tros pro pios es tu dios pre clí ni cos tien den a in di car que la MCH pro mue ve la ge ne ra ción del sue ño REM y un es ta do tipo de pre si vo. Ambos efec tos es-ta rían sien do me dia dos a tra vés de la mo du la ción de la ac ti vi dad de las neu ro nas se ro to ni nér gi cas del nú cleo dor sal del rafe. Con clu sio nes: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión.

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsib... more The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2 ± 4.8 vs. 21.6 ± 2.5 min, P < 0.05) and total NREM sleep (142.4 ± 23.2 vs. 86.5 ± 10.5 min, P < 0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

s u m m a r y The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals ... more s u m m a r y The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals predominantly in neurons located in the lateral hypothalamus and incerto-hypothalamic area. The biological function of MCH is mediated by two G-protein-coupled receptors known as MCHR1 and MCHR2, although the latter is expressed only in carnivores, primates and man. The MCHR1 couples to G i , G q and G o proteins, with G i leading to the inhibition of both excitatory and inhibitory synaptic events. Within the central nervous system (CNS) MCH participates in a number of functions including sleepewake behavior. In this respect, MCHergic neurons project widely throughout the CNS to brain regions involved in the regulation of behavioral states. MCHergic neurons are silent during wakefulness (W), increase their firing during slow wave sleep (SWS) and still more during REM sleep (REMS). Studies in knockout mice for MCH (MCH À/À) have shown a reduction in SWS and an increase of W during the light and the dark phase of the light-dark cycle. Moreover, in response to food deprivation a marked reduction in REMS time was observed in these animals. Conflicting effects on sleep variables have been reported in MCHR1 À/À mice by different authors. The i.c.v. administration of MCH increases REMS and SWS in the rat. In addition, an enhancement of REMS has been described following the microinjection of the neuropeptide into the nucleus pontis oralis of the cat, while its infusion into the dorsal raphe nucleus (DR) and the basal forebrain (horizontal limb of the diagonal band of Broca) is followed by an increase of REMS and a reduction of W in the rat. Immunoneutralization of MCH in the DR augmented W and suppressed REMS in the rat, as did the s.c. injection of selective MCHR1 antagonists. The robust REMS-inducing effect of MCH is likely related to the deactivation of monoaminergic, orexinergic, glutamatergic, cholinergic (Won) and GABAergic (REM-off) neurons involved in the generation of W and the inhibition of REMS. On the basis of preclinical studies, it can be proposed that selective MCHR1 receptor agonists could constitute potential therapeutic modalities in the arsenal of insomnia pharmacotherapy. Due to the lack of adequate animal models, the role of the MCHR2 on sleep is still unknown.

Parkinson's disease (PD) is a neurodegenerative disease secondary to the loss of dopaminergic neu... more Parkinson's disease (PD) is a neurodegenerative disease secondary to the loss of dopaminergic neurons in the substantia nigra. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces in mice and primates histopathological changes similar to PD in humans. A common feature of PD and MPTP models is neuronal death and dopamine depletion. At present the treatment of PD is principally based on the replacement of dopamine levels by administration of levodopa, however, modulation of neuronal death is important in order to modify disease progression. Silymarin is a polyphenolic flavonoid derived from the seeds and fruits of the plant Silybum marianum and has mainly antioxidant, anti-inflammatory, cytoprotective and neuroprotective effects. In order to explore whether silymarin has a neuroprotective effects in a mouse model of PD we determined the concentration of striatal dopamine by HPLC, the number of apoptotic cells, the number of tyrosine hydroxylase positive neurons (TH +) in substantia nigra by immunohistochemistry and lipid peroxidation in the striatum of vehicle-treated, silymarin-treated, MPTP-intoxicated and MPTP-silymarin treated mice. Silymarin treatment partially recovered dopamine depletion by MPTP treatment (29%–69%) compared to control group. In addition, silymarin treatment significantly reduced the number of apoptotic cells induced and preserved the number of TH + neurons of sustantia nigra after MPTP intoxication. Also, silymarin treatment reduced significantly striatal lipid peroxidation induced with MPTP treatment. The current study shows evidence of the protective properties of silymarin in a MPTP-induced PD model. Silymarin preserved striatal dopamine levels by diminishing apoptosis in the substantia nigra, preserving the TH + neurons and diminishing damage by oxidative stress. These results may be of interest in the treatment of PD. Glial cell activation and inflammatory responses may contribute to the progressive degeneration of nigral neurons in Parkinson's disease (PD). Presently, no neuroprotective therapy that successfully intervenes in the progression of the disease is available. Although apocynin possess anti-inflammatory property, clinical utility of apocynin as a neuroprotective agent is still controversial. In this study, we investigated whether mitoapocynin, a novel derivative of apocynin, could protect against glial cells mediated inflammatory reactions and nigrostriatal degeneration in cell culture and animal models of PD. First, mito-apocynin treatment in primary mesencephalic cultures significantly attenuated MPP +-induced dopaminergic neuronal loss. Interestingly, mitoapocynin also attenuated MPP +-induced glial cell proliferation, nitrotyrosine, 4-hydroxynonenol and NF-kB activation. Next, we evaluated the anti-inflammatory effect of mito-apocynin in the MPTP-induced mouse model of PD. Oral administration of mito-apocynin significantly attenuated MPTP-induced iNOS activation, microglial and astroglial cell activation, and dopaminergic neuronal damage in substantia nigra. Notably, our histological findings paralleled improved motor function and striatal dopamine depletion. Additionally, mitoapocynin treatment improved the motor deficits and dopamine depletion in the newly developed MitoPark mouse model of PD. Collectively, our results demonstrate that mitoapocynin produces distinct anti-inflammatory and neuroprotective effect in animal models of PD. These data clearly suggest that additional preclinical development of mitoapocynin may yield an effective neuroprotective drug capable of intervening in the progression of PD. (NIH grants NS39958, NS65167, NS74443).

Several cellular and molecular events responsible for the development of the central nervous syst... more Several cellular and molecular events responsible for the development of the central nervous system (CNS), particularly those related to the development of ordered neural connections, occur during the first days of postnatal life, being days 1 through 10 a critical period to reach maturity and establish innervations. We have previously characterized hypoxia-induced gene 1 (Hig-1) and described an increase in its expression from day 1 to 15 of postnatal life in the spinal cord. Hig-1 mRNA has an open reading frame for a 93 amino acid protein, but its function has not been completely elucidated. Recently, several analyses in many cell types have related Hig-1 expression with differentiation or cell death/survival balance. With the aim of further characterizing the presence of Hig-1 in the CNS, we analyzed the cellular distribution of HIG-1 protein in rat's spinal cord at postnatal days 1, 8, 15, and 90 (P1-P90). We found an interesting change in the protein expression pattern, shifting from neurons at P1 to glial cells at P90, which points towards a functional role for this protein in the spinal cord throughout development. We also compared the protein distribution with the cellular distribution of the mRNA and of an antisense RNA.

Sleep Medicine, 2009

Conclusion: These results show that sleep loss can affect sexual motivation and might lead to imp... more Conclusion: These results show that sleep loss can affect sexual motivation and might lead to important clinical implications, including alterations in female physiology and reproductive abnormalities.

Peptides, 2013

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsib... more The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5 min, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5 min, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

European Neuropsychopharmacology, 1998

Quantitation of 2 h sessions after administration of the D preferring dopamine (DA) agonist prami... more Quantitation of 2 h sessions after administration of the D preferring dopamine (DA) agonist pramipexole (10-500 mg / kg) showed 3 dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 mg / kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 mg / kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 mg / kg dose during the second recording hour. The mixed D-and D 2 3 receptor antagonist YM-09151-2 (30-500 mg / kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500-1000 mg / kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 mg / kg dose of the DA agonist. Pramipexole (30-100 mg / kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 mg / kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 mg / kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D receptor could be involved in the pramipexole-3 induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D receptor.

Brazilian Journal of Medical and Biological Research, 2001

Sea anemones are a rich source of biologically active substances. In crayfish muscle fibers, Buno... more Sea anemones are a rich source of biologically active substances. In crayfish muscle fibers, Bunodosoma cangicum whole venom selectively blocks the I K(Ca) currents. In the present study, we report for the first time powerful hemolytic and neuroactive effects present in two different fractions obtained by gel-filtration chromatography from whole venom of B. cangicum. A cytolytic fraction (Bcg-2) with components of molecular mass ranging from 8 to 18 kDa elicited hemolysis of mouse erythrocytes with an EC 50 = 14 µg/ml and a maximum dose of 22 µg/ml. The effects of the neuroactive fraction, Bcg-3 (2 to 5 kDa), were studied on isolated crab nerves. This fraction prolonged the compound action potentials by increasing their duration and rise time in a dose-dependent manner. This effect was evident after the washout of the preparation, suggesting the existence of a reversible substance that was initially masking the effects of an irreversible one. In order to elucidate the target of Bcg-3 action, the fraction was applied to a tetraethylammonium-pretreated preparation. An additional increase in action potential duration was observed, suggesting a blockade of a different population of K + channels or of tetraethylammonium-insensitive channels. Also, tetrodotoxin could not block the action potentials in a Bcg-3-pretreated preparation, suggesting a possible interaction of Bcg-3 with Na + channels. The present data suggest that B. cangicum venom contains at least two bioactive fractions whose activity on cell membranes seems to differ from the I K(Ca) blockade described previously.

Brain Research, 2008

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized within... more Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized within the postero-lateral hypothalamus and zona incerta. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes such as energy homeostasis and sleep. In the present report, we examined the distribution of MCH immunoreactivity in the brainstem of the cat. In addition to MCH+ axons, we found MCH-immunoreactive cells that have not been previously described either in the midbrain raphe nuclei or in the periaqueductal and periventricular areas. These MCH+ cells constituted: 1. ependymal cells that lined the fourth ventricle and aqueduct, 2. ependymal cells with long basal processes that projected deeply into the subventricular (subaqueductal) parenchyma, and, 3. cells in subventricular regions and the midbrain raphe nuclei. The MCH+ cells in the midbrain raphe nuclei were closely related to neuronal processes of serotonergic neurons. Utilizing Neu-N and GFAP immunohistochemistry we determined that the preceding MCH+ cells were neither neurons nor astrocytes. However, we found that vimentin, an intermediate-filament protein that is used as a marker for tanycytes, was specifically co-localized with MCH in these cells. We conclude that MCH is present in tanycytes whose processes innervate the midbrain raphe nuclei and adjacent subependymal regions. Because tanycytes are specialized cells that transport substances from the cerebrospinal fluid (CSF) to neural parenchyma, we suggest that MCH is absorbed from the CSF by tanycytes and subsequently liberate to act upon neurons of brainstem nuclei.

Behavioural Brain Research, 2011

Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown... more Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown to have antidepressant-like profile in rats. However, the mechanisms by which the MCHergic system participates in the modulation of emotional states are still to be determined. In the present study we confirmed the presence of MCHergic fibers within the dorsal raphe nucleus (DRN), a serotonergic nucleus involved in the physiopathology of major depression. We also assessed the effects of the administration of MCH and anti-MCH antibody (immunoneutralization) into the DRN using the forced swim test in rats, an animal model to screen antidepressant drugs. We found that a low dose of MCH (50 ng) evoked a depressive-like behavior indicated by a significant increase in the immobility time as well as a decrease in climbing behavior. Furthermore, the depressive-like response was prevented by pretreatment with fluoxetine. Consistent with these results, the immunoneutralization of MCH produced an antidepressant-like effect. By means of the open field test we discarded that these effects were related to unspecific changes in motor activity. Our results suggest that the MCHergic neurons are involved in the regulation of emotional behaviors through the modulation of the serotonergic neuronal activity within the DRN. In addition, the present results are in agreement with previous reports showing that antagonism of the MCHergic system may be a novel therapeutic strategy for the treatment of depressive disorders.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2015

A study was carried out on the effects of unilateral microinjection of melanin-concentrating horm... more A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep-wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

Biological Psychiatry, 1997

Melanin-concentrating hormone (MCH)-containing neurons are localized in the lateral hypothalamus ... more Melanin-concentrating hormone (MCH)-containing neurons are localized in the lateral hypothalamus and incerto-hypothalamic areas, and project to several brain regions including the dorsal raphe nucleus (DRN). The MCHergic system has been involved in the regulation of emotional states and we have demonstrated that MCH microinjections into the rat DRN promote a depressive-like state. To understand the MCHergic transmission into the DRN, in the present study we characterized the distribution and density of the MCHergic fibers along the rostro-caudal axis of the rat DRN and their anatomical relationship with the 5-HT-and GABA-containing neurons. Additionally, a functional in vivo microdialysis study was carried out in order to evaluate the MCH effects on the 5-HT extracellular levels.

Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromo-dulator are lo... more Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromo-dulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons send dense projections to the dorsal raphe nucleus (DRN). Serotonergic neurons of the DRN are involved in the control of sleep and play a critical role in major depression. Previously, we demonstrated that microinjections of MCH into the DRN resulted in an increase in REM sleep and produce a depressive-like effect. In the present study we examined the mechanisms that mediate these effects by employing neuroanatomical and electrophysiological techniques. First, we determined that rhodamine-labeled MCH (R-MCH), when microinjected into the lateral ventricle, is internalized in serotonergic and non-serotonergic DRN neurons in rats and cats. These data strongly suggest that these neurons express MCHergic receptors. Second, in rats, we demonstrated that the microinjection of MCH into the lateral ventricle results in a significant decrease in the firing rate in 59% of the neurons recorded in the DRN; the juxtacellular administration of MCH reduced the discharge in 80% of these neurons. Some of the neurons affected by MCH were likely serotonergic on the basis of their electrophysiological and pharmacological properties. We conclude that MCH reduces the activity of serotonergic neurons of the DRN. These and previous data suggest that the MCHergic modulation of serotonergic activity within the DRN is involved in the regulation of REM sleep as well as in the pathophysiology of depressive disorders.

A study was carried out on the effects of unilateral microinjection of melanin-concentrating horm... more A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep–wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lat... more Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system and play a role in sleep regulation. With the hypothesis that the MCHergic system function would be modified by the time of the day as well as by disruptions of the sleep-wake cycle, we quantified in rats the concentration of MCH in the cerebrospinal fluid (CSF), the expression of the MCH precursor (Pmch) gene in the hypothalamus, and the expression of the MCH receptor 1 (Mchr1) gene in the frontal cortex and hippocampus. These analyses were performed during paradoxical sleep deprivation (by a modified multiple platform technique), paradoxical sleep rebound and chronic sleep restriction, both at the end of the active (dark) phase (lights were turned on at Zeitgeber time zero, ZT0) and during the inactive (light) phase (ZT8). We observed that in control condition (waking and sleep ad libitum), Mchr1 gene expression was larger at ZT8 (when sleep predominates) than at ZT0, both in frontal cortex and hippocampus. In addition, compared to control, disturbances of the sleep–wake cycle produced the following effects: paradoxical sleep deprivation for 96 and 120 h reduced the expression of Mchr1 gene in frontal cortex at ZT0. Sleep rebound that followed 96 h of paradoxical sleep deprivation increased the MCH concentration in the CSF also at ZT0. Twenty-one days of sleep restriction produced a significant increment in MCH CSF levels at ZT8. Finally, sleep disruptions unveiled day/night differences in MCH CSF levels and in Pmch gene expression that were not observed in control (undisturbed) conditions. In conclusion, the time of the day and sleep disruptions produced subtle modifications in the physiology of the MCHergic system.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of... more The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.

Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has be... more Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25–100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T 30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T 30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant. Behavioural Pharmacology 25:316–324

Resumen Intro duc ción: la de pre sión ma yor (DM) es una en fer me dad psi quiá tri ca fre cuen ... more Resumen Intro duc ción: la de pre sión ma yor (DM) es una en fer me dad psi quiá tri ca fre cuen te, con im por tan te mor bi li dad y una re la ción es-tre cha con el sui ci dio. Obje ti vo: ha cer una pues ta a pun to de los avan ces en el es tu dio de la neu ro bio lo gía de la DM, en fo cán do nos en el po si ble rol de la hor mo na con cen tra do ra de me la ni na (MCH) en esta pa to lo gía. Me to do lo gía: re vi sión de la bi blio gra fía con én fa sis en nues tros pro pios tra ba jos ori gi na les. Re sul ta dos: la MCH es un neu ro mo du la dor pep tí di co sin te ti za do por neu ro nas del hi po tá la mo. Las neu ro nas MCHér gi cas en-vían pro yec cio nes ha cia di ver sas re gio nes del sis te ma ner vio so cen tral, in clu yen do las áreas vin cu la das con la re gu la ción de la vi gi lia y del sue ño, así como a di ver sas es truc tu ras del sis te ma lím bi co que par ti ci pan en la re gu la ción del hu mor. Aun que nu me-ro sos es tu dios han re la cio na do el sis te ma MCHér gi co con el con trol de la ho meos ta sis ener gé ti ca, ha llaz gos re cien tes han per-mi ti do se ña lar un rol de este sis te ma en los me ca nis mos de ge ne ra ción del sue ño. A su vez, una con ver gen cia de da tos pro ve-nien tes de di ver sos es tu dios su gie re que la MCH es ta ría in vo lu cra da en la fi sio pa to lo gía de la DM. Nues tros pro pios es tu dios pre clí ni cos tien den a in di car que la MCH pro mue ve la ge ne ra ción del sue ño REM y un es ta do tipo de pre si vo. Ambos efec tos es-ta rían sien do me dia dos a tra vés de la mo du la ción de la ac ti vi dad de las neu ro nas se ro to ni nér gi cas del nú cleo dor sal del rafe. Con clu sio nes: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión.

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsib... more The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2 ± 4.8 vs. 21.6 ± 2.5 min, P < 0.05) and total NREM sleep (142.4 ± 23.2 vs. 86.5 ± 10.5 min, P < 0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

s u m m a r y The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals ... more s u m m a r y The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals predominantly in neurons located in the lateral hypothalamus and incerto-hypothalamic area. The biological function of MCH is mediated by two G-protein-coupled receptors known as MCHR1 and MCHR2, although the latter is expressed only in carnivores, primates and man. The MCHR1 couples to G i , G q and G o proteins, with G i leading to the inhibition of both excitatory and inhibitory synaptic events. Within the central nervous system (CNS) MCH participates in a number of functions including sleepewake behavior. In this respect, MCHergic neurons project widely throughout the CNS to brain regions involved in the regulation of behavioral states. MCHergic neurons are silent during wakefulness (W), increase their firing during slow wave sleep (SWS) and still more during REM sleep (REMS). Studies in knockout mice for MCH (MCH À/À) have shown a reduction in SWS and an increase of W during the light and the dark phase of the light-dark cycle. Moreover, in response to food deprivation a marked reduction in REMS time was observed in these animals. Conflicting effects on sleep variables have been reported in MCHR1 À/À mice by different authors. The i.c.v. administration of MCH increases REMS and SWS in the rat. In addition, an enhancement of REMS has been described following the microinjection of the neuropeptide into the nucleus pontis oralis of the cat, while its infusion into the dorsal raphe nucleus (DR) and the basal forebrain (horizontal limb of the diagonal band of Broca) is followed by an increase of REMS and a reduction of W in the rat. Immunoneutralization of MCH in the DR augmented W and suppressed REMS in the rat, as did the s.c. injection of selective MCHR1 antagonists. The robust REMS-inducing effect of MCH is likely related to the deactivation of monoaminergic, orexinergic, glutamatergic, cholinergic (Won) and GABAergic (REM-off) neurons involved in the generation of W and the inhibition of REMS. On the basis of preclinical studies, it can be proposed that selective MCHR1 receptor agonists could constitute potential therapeutic modalities in the arsenal of insomnia pharmacotherapy. Due to the lack of adequate animal models, the role of the MCHR2 on sleep is still unknown.

Parkinson's disease (PD) is a neurodegenerative disease secondary to the loss of dopaminergic neu... more Parkinson's disease (PD) is a neurodegenerative disease secondary to the loss of dopaminergic neurons in the substantia nigra. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces in mice and primates histopathological changes similar to PD in humans. A common feature of PD and MPTP models is neuronal death and dopamine depletion. At present the treatment of PD is principally based on the replacement of dopamine levels by administration of levodopa, however, modulation of neuronal death is important in order to modify disease progression. Silymarin is a polyphenolic flavonoid derived from the seeds and fruits of the plant Silybum marianum and has mainly antioxidant, anti-inflammatory, cytoprotective and neuroprotective effects. In order to explore whether silymarin has a neuroprotective effects in a mouse model of PD we determined the concentration of striatal dopamine by HPLC, the number of apoptotic cells, the number of tyrosine hydroxylase positive neurons (TH +) in substantia nigra by immunohistochemistry and lipid peroxidation in the striatum of vehicle-treated, silymarin-treated, MPTP-intoxicated and MPTP-silymarin treated mice. Silymarin treatment partially recovered dopamine depletion by MPTP treatment (29%–69%) compared to control group. In addition, silymarin treatment significantly reduced the number of apoptotic cells induced and preserved the number of TH + neurons of sustantia nigra after MPTP intoxication. Also, silymarin treatment reduced significantly striatal lipid peroxidation induced with MPTP treatment. The current study shows evidence of the protective properties of silymarin in a MPTP-induced PD model. Silymarin preserved striatal dopamine levels by diminishing apoptosis in the substantia nigra, preserving the TH + neurons and diminishing damage by oxidative stress. These results may be of interest in the treatment of PD. Glial cell activation and inflammatory responses may contribute to the progressive degeneration of nigral neurons in Parkinson's disease (PD). Presently, no neuroprotective therapy that successfully intervenes in the progression of the disease is available. Although apocynin possess anti-inflammatory property, clinical utility of apocynin as a neuroprotective agent is still controversial. In this study, we investigated whether mitoapocynin, a novel derivative of apocynin, could protect against glial cells mediated inflammatory reactions and nigrostriatal degeneration in cell culture and animal models of PD. First, mito-apocynin treatment in primary mesencephalic cultures significantly attenuated MPP +-induced dopaminergic neuronal loss. Interestingly, mitoapocynin also attenuated MPP +-induced glial cell proliferation, nitrotyrosine, 4-hydroxynonenol and NF-kB activation. Next, we evaluated the anti-inflammatory effect of mito-apocynin in the MPTP-induced mouse model of PD. Oral administration of mito-apocynin significantly attenuated MPTP-induced iNOS activation, microglial and astroglial cell activation, and dopaminergic neuronal damage in substantia nigra. Notably, our histological findings paralleled improved motor function and striatal dopamine depletion. Additionally, mitoapocynin treatment improved the motor deficits and dopamine depletion in the newly developed MitoPark mouse model of PD. Collectively, our results demonstrate that mitoapocynin produces distinct anti-inflammatory and neuroprotective effect in animal models of PD. These data clearly suggest that additional preclinical development of mitoapocynin may yield an effective neuroprotective drug capable of intervening in the progression of PD. (NIH grants NS39958, NS65167, NS74443).

Several cellular and molecular events responsible for the development of the central nervous syst... more Several cellular and molecular events responsible for the development of the central nervous system (CNS), particularly those related to the development of ordered neural connections, occur during the first days of postnatal life, being days 1 through 10 a critical period to reach maturity and establish innervations. We have previously characterized hypoxia-induced gene 1 (Hig-1) and described an increase in its expression from day 1 to 15 of postnatal life in the spinal cord. Hig-1 mRNA has an open reading frame for a 93 amino acid protein, but its function has not been completely elucidated. Recently, several analyses in many cell types have related Hig-1 expression with differentiation or cell death/survival balance. With the aim of further characterizing the presence of Hig-1 in the CNS, we analyzed the cellular distribution of HIG-1 protein in rat's spinal cord at postnatal days 1, 8, 15, and 90 (P1-P90). We found an interesting change in the protein expression pattern, shifting from neurons at P1 to glial cells at P90, which points towards a functional role for this protein in the spinal cord throughout development. We also compared the protein distribution with the cellular distribution of the mRNA and of an antisense RNA.