Antonello Novelli - Academia.edu (original) (raw)

Papers by Antonello Novelli

Oxidative Medicine and Cellular Longevity, 2016

It is well recognized that mitochondrial dysfunction contributes to neurodegeneration occurring i... more It is well recognized that mitochondrial dysfunction contributes to neurodegeneration occurring in Alzheimer's disease (AD). However, evidences of mitochondrial defects in AD peripheral cells are still inconclusive. Here, some mitochondrial-encoded and nuclear-encoded proteins, involved in maintaining the correct mitochondria machine, were investigated in terms of protein expression and enzymatic activity in peripheral blood mononuclear cells (PBMCs) isolated from AD and Mild Cognitive Impairment (MCI) patients and healthy subjects. In addition mitochondrial DNA copy number was measured by real time PCR. We found some differences and some similarities between AD and MCI patients when compared with healthy subjects. For example, cytochrome C and cytochrome B were decreased in AD, while MCI showed only a statistical reduction of cytochrome C. On the other hand, both AD and MCI blood cells exhibited highly nitrated MnSOD, index of a prooxidant environment inside the mitochondria. TFAM, a regulator of mitochondrial genome replication and transcription, was decreased in both AD and MCI patients' blood cells. Moreover also the mitochondrial DNA amount was reduced in PBMCs from both patient groups. In conclusion these data confirmed peripheral mitochondria impairment in AD and demonstrated that TFAM and mtDNA amount reduction could be two features of early events occurring in AD pathogenesis.

From blood-based redox profile to the validation of a lead biomarker for the timely diagnosis of Alzheimer’s disease

Acta Neurobiologiae Experimentalis, 2017

A new and short protocol to achieve the early diagnosis of mild cognitive impairment

Neurological Sciences, 2021

Purpose The mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive... more Purpose The mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected for the age and education of the subject but are not significant enough to interfere with instrumental activities of daily living. The identification of individuals with MCI is particularly important for those who might benefit from new therapies. The aim of this work is to propose a comprehensive neuropsychological protocol to achieve early diagnosis of MCI. Methods A neuropsychological battery was created and administered to a sample of patients with MCI ( n = 25) and healthy matched controls ( n = 25). Results Although memory decline is often the first sign preceding the appearance of MCI, significant differences in visuospatial tasks, naming abilities, and executive function can be demonstrated as well between MCI and controls. Conclusions A proper selection of cognitive measures within those included in the already-available neuropsychological batteries may provide a thorough assessment of MCI and allow its timely diagnosis.

Excitatory amino acids toxicity in cerebellar granule cells in primary culture

Canada diseases weekly report = Rapport hebdomadaire des maladies au Canada, 1990

Primary cultures of cerebellar granule cells represent a valuable neuronal system for the study o... more Primary cultures of cerebellar granule cells represent a valuable neuronal system for the study of the physiology, biochemistry and toxicology of excitatory amino acids. Using this system, we now report the characterization of the biochemical and toxicological action of a toxic mussels extract, containing the excitatory amino acid domoic acid. The results obtained using toxic mussels extract, non-toxic mussels extract and purified domoic acid, provide evidence for a synergistic action of domoic acid with other potentially neurotoxic excitatory amino acids, normally present in mussels.

Potential neurotoxins: Okadaic acid and analogs

Marine Neurotoxins, 2021

Abstract Okadaic acid is a seafood toxin responsible for Diarrhetic Shellfish Poisoning (DSP) all... more Abstract Okadaic acid is a seafood toxin responsible for Diarrhetic Shellfish Poisoning (DSP) all over the world. It is a potent inhibitor of serine/threonine protein phosphatases that are present in all human organs, including the brain. In this chapter, we present and discuss the contribution that, shortly after its discovery, okadaic acid has prompted to our knowledge of the physiology and pathology of the organ that makes our history.

Organic Letters, 2020

Prorocentroic acid (PA) was isolated from the dinoflagellate Prorocentrum hoffmannianum. Relative... more Prorocentroic acid (PA) was isolated from the dinoflagellate Prorocentrum hoffmannianum. Relative configurations for its 35 asymmetric centers, were determined by analysis of NMR data including heteronuclear couplings and quantum mechanical calculations. PA was tested by using murine cortical neurons grown on microelectrode-arrays. Long term exposure to subtoxic concentrations induced a significant reorganization of neuronal signaling, mainly by changes in the bursting activity. The observed effects could be due to the activation of a plasticity process.

Alzheimer's & Dementia, 2017

Toxicological Sciences, 2013

Okadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structu... more Okadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structure analysis of the isolated OKA analogue 19-epi-OKA showed important conformation differences expected to result in lower protein phosphatase (PP) inhibitory potencies than OKA. However, 19-epi-OKA and OKA inhibitory activities versus PP2A were unexpectedly found to be virtually equipotent. To investigate the toxicological relevance of these findings, we tested the effects of 19-epi-OKA on cultured cerebellar cells and compared them with those of OKA and its isomer dinophysistoxin-2. 19-epi-OKA caused degeneration of neurites and neuronal death with much lower potency than its congeners. The concentration of 19-epi-OKA that reduced after 24 h the maximum neuronal survival (EC50 24) by 50% was ~300nM compared with ~2nM and ~8nM for OKA and dinophysistoxin-2, respectively. Exposure to 19-epi-OKA resulted also in less toxicity for cultured glial cells (EC50 24,19-epi-OKA ~ 600nM; EC50 24,OKA ~ 20nM). 19-epi-OKA induced apoptotic condensation and fragmentation of chromatin, activation of caspases, and activation of ERK1/2 MAP kinases, features previously reported for OKA and dinophysistoxin-2. Also, differential sensitivity to 19-epi-OKA was observed between neuronal and glial cells, a specific characteristic shared by OKA and dinophysistoxin-2 but not by other toxins. Our results are consistent with 19-epi-OKA being included among the group of toxins of OKA and derivatives and support the suitability of cellular bioassays for the detection of these compounds.

Nuclear factor κB is a critical determinant in N-methyl-d-aspartate receptor-mediated neuroprotection

Journal of Neurochemistry, 2001

Nuclear factor kB is a critical determinant in ... N-methyl-D-aspartate receptor-mediated neuropr... more Nuclear factor kB is a critical determinant in ... N-methyl-D-aspartate receptor-mediated neuroprotection ... Robert H. Lipsky,* Ke Xu,* Daming Zhu,² Charles Kelly,² Artin Terhakopian,² Antonello Novelli³ and Ann M. Marini² ... *Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland, ...

Acta Endocrinologica, 1984

Prolactin (Prl) and growth hormone (GH) responses to different pharmacologic probes acting at the... more Prolactin (Prl) and growth hormone (GH) responses to different pharmacologic probes acting at the central nervous system (CNS) or the anterior pituitary (AP) level were evaluated in patients with distinct neuroendocrine disorders. Thirteen patients with Prl-secreting tumours (PST), 10 acromegalics (A) and 8 patients with

Brain Research Bulletin, 1996

A new method for quantitative determination of cytochrome oxidase (C.O.) activity was applied to ... more A new method for quantitative determination of cytochrome oxidase (C.O.) activity was applied to diencephalic structures of the limbic system that are closely connected anatomically, that is, the mammillary bodies (MB) and the anterior nucleus of the thalamus (AT), This method makes it possible to easily evaluate the oxidative metabolic capacity of brain regions, an index of their functionality. By using this technique, we studied the postnatal development of both structures in Wistar rats of 14, 21, 30, and 120 days of age. Furthermore, animals of 730 days were included in order to evaluate the effects of aging on C.O. activity of these structures. The results showed a significant increase in the C.O. activity of the subdivisions of the AT, its levels remaining constant until the adult age, with a significant decrease in its activity in aged animals. In the MB, only the increase in C.O. activity of the medial mammillary nucleus (pars medialis) was significant until the adult age. A decrease of C.O. values with aging was significant only in the lateral mammillary nucleus. These data suggest that there is a wide heterogeneity in the maturation and aging of brain oxidative metabolism in diencaphalic structures.

Brain Research, 1999

The mechanisms by which aluminum interacts with the nervous system are only partly understood. In... more The mechanisms by which aluminum interacts with the nervous system are only partly understood. In this study, we used cultured Ž. astrocytes and neurons to investigate the effects of long exposures to aluminum 1 mM. We found that aluminum accumulated both in neurons and astrocytes. After 8-12 days exposure, aluminum caused strong changes in the morphology of astrocytes including shrinkage of cell bodies and retraction of processes. Exposures over 15-18 days reduced astrocytes viability by 50%. Aluminum-induced degeneration of astrocytes involved the DNA fragmentation characteristic of apoptosis, and staining of aluminum-treated astrocytes with the DNA-binding fluorochrome Hoeschst 33258 revealed the typical apoptotic condensation and fragmentation of chromatin. Aluminum Ž. Ž. was also found to be neurotoxic, causing first 4-6 days abnormal clustering and aggregation, and later 8-12 days neuronal death. Interestingly, aluminum neurotoxicity occurred in neuroglial cultures containing approximately 10% astrocytes but not in near-pure neuronal cultures containing only 1% astrocytes. Staining of co-cultured cells with Hoeschst 33258 showed apoptotic condensation and fragmentation of chromatin in aluminum-treated astrocytes but not in co-cultured neurons. Our study demonstrates that aluminum can induce the apoptotic degeneration of astrocytes, and that this toxicity is critical in determining neuronal degeneration and death. Aluminum-mediated apoptosis of cultured astrocytes may be also a valuable model system to study the mechanisms underlying apoptosis in glial cells.

Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation

Amino Acids, 2006

Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling bo... more Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling both neuropathic pain and convulsions in rodents. In this study we compared nefopam to carbamazepine (CBZ), a reference antiepileptic drug (AED), for their ability to protect cerebellar neuronal cultures from neurodegeneration induced by veratridine (VTD). Furthermore, we tested nefopam for protection against both, maximal electroshock-induced seizures (MES), and isoniazid-induced seizures in mice. Both NEF and CBZ were effective in preventing both signs of excitotoxicity and neurodegeneration following exposure of cultures to 5 microM veratridine for 30 min and 24 h, respectively. Concentrations providing full neuroprotection were 500 microM CBZ and 50 microM NEF, while the concentration providing 50% neuroprotection was 200 microM for CBZ and 20 microM for NEF. Neither NEF nor CBZ reduced excitotoxicity following direct exposure of cultures to glutamate, but CBZ failed to reduce increases in intracellular calcium following stimulation of L-type voltage sensitive calcium channels. In vivo, NEF (20 mg/kg i.p.) significantly reduced MES and fully prevented MES-induced terminal clonus (TC). In comparison, NEF was significantly more effective than CBZ in preventing MES, although both drugs were equally effective against MES-induced TC. Furthermore, nefopam provided protection against isoniazid-induced seizures at doses similar to those protecting against MES.

Preconditioning and neurotrophins: a model for brain adaptation to seizures, ischemia and other stressful stimuli

Amino Acids, 2006

The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, ac... more The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, activates receptors coupled to calcium influx. Excessive activation of glutamate receptors in conditions such as severe epileptic seizures or stroke can kill neurons in a process called excitotoxicity. However, subtoxic levels of activation of the N-methyl-D-aspartate (NMDA) type of glutamate receptor elicit adaptive responses in neurons that enhance their ability to withstand more severe stress. A variety of stimuli induce adaptive responses to protect neurons. For example, sublethal ischemic episodes or a mild epileptic insult can protect neurons in a process referred to as tolerance. The molecular mechanisms that protect neurons by these different stressful stimuli are largely unknown but they share common features such as the transcription factor, nuclear factor kappa B (NF-kappaB), which is activated by ischemic and epileptic preconditioning as well as exposure to subtoxic NMDA concentrations. In this article, we describe stress-induced neuroprotective mechanisms highlighting the role of brain-derived neurotrophic factor (BDNF), a protein that plays a crucial role in neuronal survival and maintenance, neurogenesis and learning and memory.

Journal of Neurotrauma, 2003

How to join PubMed Commons NCBI is currently redirecting web traffic to HTTPS. Read more about ou... more How to join PubMed Commons NCBI is currently redirecting web traffic to HTTPS. Read more about our https testing.

Alzheimer's & Dementia, 2010

30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NI... more 30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria. We measured the glycosylation of serum glycproteins using lectin blot analysis and improved lectin enzyme-linked immunosorbent assay. The study was approved by the Tottori University Ethical Committee and informed consent was obtained from each patient or their relatives prior to inclusion in the study. The study was performed in accordance with the Helsinki Declaration. Results: We identified several kinds of sugar chain in some serum glycoproteins were altered in AD patients compared with NDC groups. And these changes were observed in early stage of AD. Conclusions: These data implicate glycosylation changes in AD patients are potential biological markers to diagnose with serum. Moreover, the aberrations are prospective to detect the initial phase of AD.

Pérez-Gómez et al., 1 The marine toxin dinophysistoxin-2 induces differential apoptotic death of rat

Toxicological Sciences, Sep 25, 2017

Domoic acid (DOM) is an excitatory amino acid analog of kainic acid (KA) that acts through glutam... more Domoic acid (DOM) is an excitatory amino acid analog of kainic acid (KA) that acts through glutamic acid (GLU) receptors, inducing a fast and potent neurotoxic response. Here, we present evidence for an enhancement of excitotoxicity following exposure of cultured cerebellar granule cells to DOM in the presence of lower than physiological Na þ concentrations. The concentration of DOM that reduced by 50% neuronal survival was approximately 3 mM in Na þ-free conditions and 16 mM in presence of a physiological concentration of extracellular Na þ. The enhanced neurotoxic effect of DOM was fully prevented by AMPA/KA receptor antagonist, while N-methyl-D-aspartate-receptor-mediated neurotoxicity did not seem to be involved, as the absence of extracellular Na þ failed to potentiate GLU excitotoxicity under the same experimental conditions. Lowering of extracellular Na þ concentration to 60 mM eliminated extracellular recording of spontaneous electrophysiological activity from cultured neurons grown on a multi electrode array and prevented DOM stimulation of the electrical activity. Although changes in the extracellular Na þ concentration did not alter the magnitude of the rapid increase in intracellular Ca 2þ levels associated to DOM exposure, they did change significantly the contribution of voltagesensitive calcium channels (VScaCs) and the recovery time to baseline. The prevention of Ca 2þ influx via VSCaCs by nifedipine failed to prevent DOM toxicity at any extracellular Na þ concentration, while the reduction of extracellular Ca 2þ concentration ameliorated DOM toxicity only in the absence of extracellular Na þ , enhancing it in physiological conditions. Our data suggest a crucial role for extracellular Na þ concentration in determining excitotoxicity by DOM.

Potential neurotoxins: Palytoxins

Marine Neurotoxins, 2021

Palytoxin has been long associated to the ingestion of contaminated food in tropical coastal area... more Palytoxin has been long associated to the ingestion of contaminated food in tropical coastal areas. In the last years, however, the increasing number of reports of poisonings among beachgoers due to the inhalation of contaminated aerosols during Ostreopsis blooms, or affecting aquarium hobbyists and workers as a result of exposure to palytoxin-containing soft corals during maintenance of home reef aquaria, have risen serious concern about the hazard that these compounds may pose for human health. Interaction of palytoxin with its main molecular biological target, the Na+/K+-ATPase, transforms the pump into a non-selective channel permeable to monovalent cations, disrupting cellular ionic homeostasis and eventually determining cell death. Given the key role of Na+/K+-ATPase in maintaining neuronal survival and functioning, the central nervous system appears to be particularly vulnerable to these toxins. By using primary culture experimental systems, we describe the molecular mechanis...

Oxidative Medicine and Cellular Longevity, 2016

It is well recognized that mitochondrial dysfunction contributes to neurodegeneration occurring i... more It is well recognized that mitochondrial dysfunction contributes to neurodegeneration occurring in Alzheimer's disease (AD). However, evidences of mitochondrial defects in AD peripheral cells are still inconclusive. Here, some mitochondrial-encoded and nuclear-encoded proteins, involved in maintaining the correct mitochondria machine, were investigated in terms of protein expression and enzymatic activity in peripheral blood mononuclear cells (PBMCs) isolated from AD and Mild Cognitive Impairment (MCI) patients and healthy subjects. In addition mitochondrial DNA copy number was measured by real time PCR. We found some differences and some similarities between AD and MCI patients when compared with healthy subjects. For example, cytochrome C and cytochrome B were decreased in AD, while MCI showed only a statistical reduction of cytochrome C. On the other hand, both AD and MCI blood cells exhibited highly nitrated MnSOD, index of a prooxidant environment inside the mitochondria. TFAM, a regulator of mitochondrial genome replication and transcription, was decreased in both AD and MCI patients' blood cells. Moreover also the mitochondrial DNA amount was reduced in PBMCs from both patient groups. In conclusion these data confirmed peripheral mitochondria impairment in AD and demonstrated that TFAM and mtDNA amount reduction could be two features of early events occurring in AD pathogenesis.

From blood-based redox profile to the validation of a lead biomarker for the timely diagnosis of Alzheimer’s disease

Acta Neurobiologiae Experimentalis, 2017

A new and short protocol to achieve the early diagnosis of mild cognitive impairment

Neurological Sciences, 2021

Purpose The mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive... more Purpose The mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected for the age and education of the subject but are not significant enough to interfere with instrumental activities of daily living. The identification of individuals with MCI is particularly important for those who might benefit from new therapies. The aim of this work is to propose a comprehensive neuropsychological protocol to achieve early diagnosis of MCI. Methods A neuropsychological battery was created and administered to a sample of patients with MCI ( n = 25) and healthy matched controls ( n = 25). Results Although memory decline is often the first sign preceding the appearance of MCI, significant differences in visuospatial tasks, naming abilities, and executive function can be demonstrated as well between MCI and controls. Conclusions A proper selection of cognitive measures within those included in the already-available neuropsychological batteries may provide a thorough assessment of MCI and allow its timely diagnosis.

Excitatory amino acids toxicity in cerebellar granule cells in primary culture

Canada diseases weekly report = Rapport hebdomadaire des maladies au Canada, 1990

Primary cultures of cerebellar granule cells represent a valuable neuronal system for the study o... more Primary cultures of cerebellar granule cells represent a valuable neuronal system for the study of the physiology, biochemistry and toxicology of excitatory amino acids. Using this system, we now report the characterization of the biochemical and toxicological action of a toxic mussels extract, containing the excitatory amino acid domoic acid. The results obtained using toxic mussels extract, non-toxic mussels extract and purified domoic acid, provide evidence for a synergistic action of domoic acid with other potentially neurotoxic excitatory amino acids, normally present in mussels.

Potential neurotoxins: Okadaic acid and analogs

Marine Neurotoxins, 2021

Abstract Okadaic acid is a seafood toxin responsible for Diarrhetic Shellfish Poisoning (DSP) all... more Abstract Okadaic acid is a seafood toxin responsible for Diarrhetic Shellfish Poisoning (DSP) all over the world. It is a potent inhibitor of serine/threonine protein phosphatases that are present in all human organs, including the brain. In this chapter, we present and discuss the contribution that, shortly after its discovery, okadaic acid has prompted to our knowledge of the physiology and pathology of the organ that makes our history.

Organic Letters, 2020

Prorocentroic acid (PA) was isolated from the dinoflagellate Prorocentrum hoffmannianum. Relative... more Prorocentroic acid (PA) was isolated from the dinoflagellate Prorocentrum hoffmannianum. Relative configurations for its 35 asymmetric centers, were determined by analysis of NMR data including heteronuclear couplings and quantum mechanical calculations. PA was tested by using murine cortical neurons grown on microelectrode-arrays. Long term exposure to subtoxic concentrations induced a significant reorganization of neuronal signaling, mainly by changes in the bursting activity. The observed effects could be due to the activation of a plasticity process.

Alzheimer's & Dementia, 2017

Toxicological Sciences, 2013

Okadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structu... more Okadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structure analysis of the isolated OKA analogue 19-epi-OKA showed important conformation differences expected to result in lower protein phosphatase (PP) inhibitory potencies than OKA. However, 19-epi-OKA and OKA inhibitory activities versus PP2A were unexpectedly found to be virtually equipotent. To investigate the toxicological relevance of these findings, we tested the effects of 19-epi-OKA on cultured cerebellar cells and compared them with those of OKA and its isomer dinophysistoxin-2. 19-epi-OKA caused degeneration of neurites and neuronal death with much lower potency than its congeners. The concentration of 19-epi-OKA that reduced after 24 h the maximum neuronal survival (EC50 24) by 50% was ~300nM compared with ~2nM and ~8nM for OKA and dinophysistoxin-2, respectively. Exposure to 19-epi-OKA resulted also in less toxicity for cultured glial cells (EC50 24,19-epi-OKA ~ 600nM; EC50 24,OKA ~ 20nM). 19-epi-OKA induced apoptotic condensation and fragmentation of chromatin, activation of caspases, and activation of ERK1/2 MAP kinases, features previously reported for OKA and dinophysistoxin-2. Also, differential sensitivity to 19-epi-OKA was observed between neuronal and glial cells, a specific characteristic shared by OKA and dinophysistoxin-2 but not by other toxins. Our results are consistent with 19-epi-OKA being included among the group of toxins of OKA and derivatives and support the suitability of cellular bioassays for the detection of these compounds.

Nuclear factor κB is a critical determinant in N-methyl-d-aspartate receptor-mediated neuroprotection

Journal of Neurochemistry, 2001

Nuclear factor kB is a critical determinant in ... N-methyl-D-aspartate receptor-mediated neuropr... more Nuclear factor kB is a critical determinant in ... N-methyl-D-aspartate receptor-mediated neuroprotection ... Robert H. Lipsky,* Ke Xu,* Daming Zhu,² Charles Kelly,² Artin Terhakopian,² Antonello Novelli³ and Ann M. Marini² ... *Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland, ...

Acta Endocrinologica, 1984

Prolactin (Prl) and growth hormone (GH) responses to different pharmacologic probes acting at the... more Prolactin (Prl) and growth hormone (GH) responses to different pharmacologic probes acting at the central nervous system (CNS) or the anterior pituitary (AP) level were evaluated in patients with distinct neuroendocrine disorders. Thirteen patients with Prl-secreting tumours (PST), 10 acromegalics (A) and 8 patients with

Brain Research Bulletin, 1996

A new method for quantitative determination of cytochrome oxidase (C.O.) activity was applied to ... more A new method for quantitative determination of cytochrome oxidase (C.O.) activity was applied to diencephalic structures of the limbic system that are closely connected anatomically, that is, the mammillary bodies (MB) and the anterior nucleus of the thalamus (AT), This method makes it possible to easily evaluate the oxidative metabolic capacity of brain regions, an index of their functionality. By using this technique, we studied the postnatal development of both structures in Wistar rats of 14, 21, 30, and 120 days of age. Furthermore, animals of 730 days were included in order to evaluate the effects of aging on C.O. activity of these structures. The results showed a significant increase in the C.O. activity of the subdivisions of the AT, its levels remaining constant until the adult age, with a significant decrease in its activity in aged animals. In the MB, only the increase in C.O. activity of the medial mammillary nucleus (pars medialis) was significant until the adult age. A decrease of C.O. values with aging was significant only in the lateral mammillary nucleus. These data suggest that there is a wide heterogeneity in the maturation and aging of brain oxidative metabolism in diencaphalic structures.

Brain Research, 1999

The mechanisms by which aluminum interacts with the nervous system are only partly understood. In... more The mechanisms by which aluminum interacts with the nervous system are only partly understood. In this study, we used cultured Ž. astrocytes and neurons to investigate the effects of long exposures to aluminum 1 mM. We found that aluminum accumulated both in neurons and astrocytes. After 8-12 days exposure, aluminum caused strong changes in the morphology of astrocytes including shrinkage of cell bodies and retraction of processes. Exposures over 15-18 days reduced astrocytes viability by 50%. Aluminum-induced degeneration of astrocytes involved the DNA fragmentation characteristic of apoptosis, and staining of aluminum-treated astrocytes with the DNA-binding fluorochrome Hoeschst 33258 revealed the typical apoptotic condensation and fragmentation of chromatin. Aluminum Ž. Ž. was also found to be neurotoxic, causing first 4-6 days abnormal clustering and aggregation, and later 8-12 days neuronal death. Interestingly, aluminum neurotoxicity occurred in neuroglial cultures containing approximately 10% astrocytes but not in near-pure neuronal cultures containing only 1% astrocytes. Staining of co-cultured cells with Hoeschst 33258 showed apoptotic condensation and fragmentation of chromatin in aluminum-treated astrocytes but not in co-cultured neurons. Our study demonstrates that aluminum can induce the apoptotic degeneration of astrocytes, and that this toxicity is critical in determining neuronal degeneration and death. Aluminum-mediated apoptosis of cultured astrocytes may be also a valuable model system to study the mechanisms underlying apoptosis in glial cells.

Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation

Amino Acids, 2006

Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling bo... more Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling both neuropathic pain and convulsions in rodents. In this study we compared nefopam to carbamazepine (CBZ), a reference antiepileptic drug (AED), for their ability to protect cerebellar neuronal cultures from neurodegeneration induced by veratridine (VTD). Furthermore, we tested nefopam for protection against both, maximal electroshock-induced seizures (MES), and isoniazid-induced seizures in mice. Both NEF and CBZ were effective in preventing both signs of excitotoxicity and neurodegeneration following exposure of cultures to 5 microM veratridine for 30 min and 24 h, respectively. Concentrations providing full neuroprotection were 500 microM CBZ and 50 microM NEF, while the concentration providing 50% neuroprotection was 200 microM for CBZ and 20 microM for NEF. Neither NEF nor CBZ reduced excitotoxicity following direct exposure of cultures to glutamate, but CBZ failed to reduce increases in intracellular calcium following stimulation of L-type voltage sensitive calcium channels. In vivo, NEF (20 mg/kg i.p.) significantly reduced MES and fully prevented MES-induced terminal clonus (TC). In comparison, NEF was significantly more effective than CBZ in preventing MES, although both drugs were equally effective against MES-induced TC. Furthermore, nefopam provided protection against isoniazid-induced seizures at doses similar to those protecting against MES.

Preconditioning and neurotrophins: a model for brain adaptation to seizures, ischemia and other stressful stimuli

Amino Acids, 2006

The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, ac... more The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, activates receptors coupled to calcium influx. Excessive activation of glutamate receptors in conditions such as severe epileptic seizures or stroke can kill neurons in a process called excitotoxicity. However, subtoxic levels of activation of the N-methyl-D-aspartate (NMDA) type of glutamate receptor elicit adaptive responses in neurons that enhance their ability to withstand more severe stress. A variety of stimuli induce adaptive responses to protect neurons. For example, sublethal ischemic episodes or a mild epileptic insult can protect neurons in a process referred to as tolerance. The molecular mechanisms that protect neurons by these different stressful stimuli are largely unknown but they share common features such as the transcription factor, nuclear factor kappa B (NF-kappaB), which is activated by ischemic and epileptic preconditioning as well as exposure to subtoxic NMDA concentrations. In this article, we describe stress-induced neuroprotective mechanisms highlighting the role of brain-derived neurotrophic factor (BDNF), a protein that plays a crucial role in neuronal survival and maintenance, neurogenesis and learning and memory.

Journal of Neurotrauma, 2003

How to join PubMed Commons NCBI is currently redirecting web traffic to HTTPS. Read more about ou... more How to join PubMed Commons NCBI is currently redirecting web traffic to HTTPS. Read more about our https testing.

Alzheimer's & Dementia, 2010

30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NI... more 30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria. We measured the glycosylation of serum glycproteins using lectin blot analysis and improved lectin enzyme-linked immunosorbent assay. The study was approved by the Tottori University Ethical Committee and informed consent was obtained from each patient or their relatives prior to inclusion in the study. The study was performed in accordance with the Helsinki Declaration. Results: We identified several kinds of sugar chain in some serum glycoproteins were altered in AD patients compared with NDC groups. And these changes were observed in early stage of AD. Conclusions: These data implicate glycosylation changes in AD patients are potential biological markers to diagnose with serum. Moreover, the aberrations are prospective to detect the initial phase of AD.

Pérez-Gómez et al., 1 The marine toxin dinophysistoxin-2 induces differential apoptotic death of rat

Toxicological Sciences, Sep 25, 2017

Domoic acid (DOM) is an excitatory amino acid analog of kainic acid (KA) that acts through glutam... more Domoic acid (DOM) is an excitatory amino acid analog of kainic acid (KA) that acts through glutamic acid (GLU) receptors, inducing a fast and potent neurotoxic response. Here, we present evidence for an enhancement of excitotoxicity following exposure of cultured cerebellar granule cells to DOM in the presence of lower than physiological Na þ concentrations. The concentration of DOM that reduced by 50% neuronal survival was approximately 3 mM in Na þ-free conditions and 16 mM in presence of a physiological concentration of extracellular Na þ. The enhanced neurotoxic effect of DOM was fully prevented by AMPA/KA receptor antagonist, while N-methyl-D-aspartate-receptor-mediated neurotoxicity did not seem to be involved, as the absence of extracellular Na þ failed to potentiate GLU excitotoxicity under the same experimental conditions. Lowering of extracellular Na þ concentration to 60 mM eliminated extracellular recording of spontaneous electrophysiological activity from cultured neurons grown on a multi electrode array and prevented DOM stimulation of the electrical activity. Although changes in the extracellular Na þ concentration did not alter the magnitude of the rapid increase in intracellular Ca 2þ levels associated to DOM exposure, they did change significantly the contribution of voltagesensitive calcium channels (VScaCs) and the recovery time to baseline. The prevention of Ca 2þ influx via VSCaCs by nifedipine failed to prevent DOM toxicity at any extracellular Na þ concentration, while the reduction of extracellular Ca 2þ concentration ameliorated DOM toxicity only in the absence of extracellular Na þ , enhancing it in physiological conditions. Our data suggest a crucial role for extracellular Na þ concentration in determining excitotoxicity by DOM.

Potential neurotoxins: Palytoxins

Marine Neurotoxins, 2021

Palytoxin has been long associated to the ingestion of contaminated food in tropical coastal area... more Palytoxin has been long associated to the ingestion of contaminated food in tropical coastal areas. In the last years, however, the increasing number of reports of poisonings among beachgoers due to the inhalation of contaminated aerosols during Ostreopsis blooms, or affecting aquarium hobbyists and workers as a result of exposure to palytoxin-containing soft corals during maintenance of home reef aquaria, have risen serious concern about the hazard that these compounds may pose for human health. Interaction of palytoxin with its main molecular biological target, the Na+/K+-ATPase, transforms the pump into a non-selective channel permeable to monovalent cations, disrupting cellular ionic homeostasis and eventually determining cell death. Given the key role of Na+/K+-ATPase in maintaining neuronal survival and functioning, the central nervous system appears to be particularly vulnerable to these toxins. By using primary culture experimental systems, we describe the molecular mechanis...