Edward Neafsey | Loyola University Medical Center (original) (raw)
Papers by Edward Neafsey
Brain Research, 1986
In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patch... more In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patches of cortex devoted to particular movements. The location of major subdivisions such as the forelimb or hindlimb areas is somatotopic and is consistent from animal to animal, but the internal organization of the pattern of movements represented within major subdivisions varies significantly between animals. The motor cortex includes both agranular primary motor cortex (AgL) and, in addition, a significant amount of the bordering granular somatic sensory cortex (Gr(SI)), as well as the rostral portion of the taste sensory insular or claustrocortex (Cl). The rat frontal cortex also contains a second, rostral motor representation of the forelimb, trunk and hindlimb, which is somatotopically organized and may be the rat's supplementary motor area. Both of these motor representations give rise to direct corticospinal projections, some of which may make monosynaptic connections with cervical enlargement motoneurons. Medial to the primary motor cortex, in cytoarchitectonic field AgM, is what appears to be part of the rat's frontal eye fields, a region which also includes the vibrissae motor representation. The somatic motor cortical output organization pattern in the rat is remarkably similar to that seen in the primate, whose primary, supplementary and frontal eye field cortical motor regions have been extensively studied.
We previously reported anatomical plasticity in the adult motor cortex after a unilateral sensori... more We previously reported anatomical plasticity in the adult motor cortex after a unilateral sensorimotor cortex (SMC) lesion and treatment with monoclonal antibody (mAb) IN-1, which permits neurite outgrowth from the intact, opposite cortex into deafferented subcortical targets. This study was designed to investigate whether treatment with the mAb IN-1 after SMC lesion in the adult leads to functional reorganization of the intact, opposite motor cortex. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or control antibody, or no treatment. After a 6 week survival period, the intact, opposite forelimb motor cortex was explored using intracortical microstimulation to evoke forelimb movements. A dramatic increase in ipsilateral movements of the lesion-impaired forelimb was found in animals treated with mAb IN-1 compared with control animals. These results resembled our previous findings of cortical reorganization in the spared hemisphere after neonatal cortical lesion and without any additional treatment. These results show that, after adult cortical lesion, treatment with mAb IN-1 induces a functional reorganization of the intact, opposite motor cortex.
Experimental Neurology, 2006
Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulte... more Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulted in an apparent shift of the motor cortex map in the spared hemisphere, particularly of the hindlimb cortex. In view of such findings, the present study was initiated to determine if the visual cortex located both ipsilateral and contralateral to neonatal SMC, or contralateral to occipital cortical (OC) lesions, would show similar remodeling. Visual evoked potentials (VEPs) were used to map the visual cortex electrophysiologically. The results show an expansion of the visual cortex, in both the contralateral and ipsilateral hemisphere, into normally motor cortical areas in adult animals that had sustained unilateral neonatal unilateral SMC lesions. In contrast, similar changes were not seen within the spared visual cortex after unilateral occipital cortical lesions, suggesting that the shift in the visual map was specifically in response to the SMC lesion and was not a generalized response to neonatal cortical damage. Histological analysis showed a functional expansion in the rostral boundary of visual cortex with no corresponding cytoarchitectural alterations.
Experimental Neurology, 1979
Single-unit recordings were made in the entopeduncular nucleus of cats which had previously under... more Single-unit recordings were made in the entopeduncular nucleus of cats which had previously undergone ipsilateral caudate lesions. During penicillin-induced epileptiform discharge from the pericruciate cortex, the percentage of responsive entopeduncular neurons in animals with a lesion was less than 20%. In a previous study in intact cats and in control experiments in the present study the percentage of responsive entopeduncular cells was more than 75%. These results indicate that propagation of epileptic discharge through the basal ganglia depends on intact pathways from the cortex to the caudate and from the caudate to the entopeduncular nucleus.
Neurochemical Research, 1997
The activity of β-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methyl... more The activity of β-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated β-carbolinium compounds. We have hypothesized that these N-methylated β-carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain β-carboline-2-N-methyltransferase activity. The activity of β-carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5–9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 μM and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 μM and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals.
Journal of Neurochemistry, 2004
Endogenous or exogenous β-carboline (βC) derivatives structurally related to the selective dopami... more Endogenous or exogenous β-carboline (βC) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) may contribute to dopaminergic neurodegeneration in Parkinson's disease (PD). We addressed the importance of the dopamine transporter (DAT) for selective dopaminergic toxicity by testing the differential cytotoxicity and cellular uptake of 12 βCs in human embryonic kidney HEK-293 cells ectopically expressing the DAT gene. Cell death was measured using [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays, and uptake by a fluorescence-based uptake assay. All βCs and MPP+ showed general cytotoxicity in parental HEK-293 cells after 72 h with half-maximal toxic concentrations (TC50 values) in the upper micromolar range. Besides MPP+, only 2[N]-methylated compounds showed enhanced cytotoxicity in DAT expressing HEK-293 cells with 1.3- to 4.5-fold reduction of TC50 values compared with parental cell line. The rank order of selectivity was: MPP+ >> 2[N],9[N]-dimethyl-harminium > 2[N]-methyl-harminium > 2[N],9[N]-dimethyl-harmanium = 2[N]-methyl-norharmanium > 2[N]-methyl-harmanium > 2[N],9[N]-dimethyl-norharminium. Consistently, only 2[N]-methylated βCs were transported into the cell through the DAT with up to five times greater Km and 12–220 times smaller Vmax values compared with dopamine and MPP+. There was a weak relation of DAT-mediated selectivity with the affinity of βCs at the DAT (Km), but not with Vmax. Our data suggest that DAT-mediated cellular uptake of 2[N]-methylated βCs represents a potential mechanism for selective toxicity towards dopaminergic neurons and may be relevant for the pathogenesis of Parkinson's disease.
Neuroreport, 2004
ABSTRACT Consumers of moderate amounts of ethanol have a lower risk of Alzheimer's dement... more ABSTRACT Consumers of moderate amounts of ethanol have a lower risk of Alzheimer's dementia than do abstainers. In Alzheimer's disease the brain contains many extracellular plaques composed of amyloid-beta (Abeta), a neurotoxic protein linked to pathogenesis of the disease. Here we report that moderate ethanol preconditioning (20-30 mM for 6 days) of organotypic hippocampal-entorhinal slice cultures prevents Abeta-induced neurotoxicity and apoptosis as measured by media lactate dehydrogenase levels and staining with propidium iodide and Hoechst 33342. With Abeta, as with our previous studies of the neurotoxic HIV-I protein gp120, moderate ethanol preconditioning may interfere with various glial-mediated neurotoxic responses in the slices to A. In addition, we found that moderate ethanol preconditioning causes an almost 3-fold increase in brain levels of heat shock protein 70 (hsp70), a protective molecular chaperone. Our results suggest possible molecular mechanisms underlying the protective effect of moderate drinking against Alzheimer's dementia.
Neurobiology of Disease, 2000
Enzymatic -carboline N-methyltransferase activities generate N-methylated -carbolinium cations ... more Enzymatic -carboline N-methyltransferase activities generate N-methylated -carbolinium cations that are analogs of the parkinsonian-producing neurotoxin MPP؉. We measured -carboline-2Nmethyltransferase and -carboline-9N-methyltransferase activities in the supernatant and particulate fractions from postmortem human brains. These N-methyltransferase activities were assessed in the substantia nigra, putamen, and frontal cortex from control and Parkinson's disease cases. No significant differences were measured in any brain region in particulate and supernatant fraction -carboline 2N-methyltransferase activity or particulate fraction -carboline 9N-methyltransferase activity. Likewise, supernatant fraction -carboline 9N-methyltransferase activity was similar in the putamen and substantia nigra from Parkinson's disease and control cases. Unexpectedly, supernatant fraction -carboline 9N-methyltransferase activity was increased fourfold in Parkinson's disease frontal cortex (P < 0.05), suggesting that -carboline N-methylation may play a role in Parkinson's disease.
Neurochemical Research, 2009
Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether p... more Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether phospholipase A2 (PLA2) activity is involved in binge alcohol (ethanol)-induced neurodegeneration, and whether docosahexaenoic acid (DHA; 22:6n-3), a fish oil-enriched fatty acid that is anti-inflammatory in brain damage models, is neuroprotective. Assessed with propidium iodide and lactate dehydrogenase (LDH) leakage, neurodamage from ethanol (6 days 100 mM ethanol with four withdrawal periods) was prevented by the PLA2 pan-inhibitor, mepacrine. Also, ethanol-dependent neurodegeneration—particularly in the entorhinal region—was significantly ameliorated by DHA supplementation (25 μM); however, adrenic acid, a 22:4n-6 analog, was ineffective. Consistent with PLA2 activation, [3H] liberation was approximately fivefold greater in [3H]arachidonic acid-preloaded HEC slice cultures during ethanol withdrawal compared to controls, and DHA supplementation suppressed [3H] release to control levels. DHA might antagonize PLA2 activity directly or suppress upstream activators (e.g., oxidative stress); however, other DHA mechanisms could be important in subdueing ethanol-induced PLA2-dependent and independent neuroinflammatory processes.
Neurochemistry International, 2002
Mammalian brain has a -carboline 2N-methyltransferase activity that converts -carbolines, such ... more Mammalian brain has a -carboline 2N-methyltransferase activity that converts -carbolines, such as norharman and harman, into 2N-methylated -carbolinium cations, which are structural and functional analogs of the Parkinsonian-inducing toxin 1-methyl-4phenylpyridinium cation (MPP + ). The identity and physiological function of this -carboline 2N-methylation activity was previously unknown. We report pharmacological and biochemical evidence that phenylethanolamine N-methyltransferase (EC 2.1.1.28) has -carboline 2N-methyltransferase activity. Specifically, purified phenylethanolamine N-methyltransferase (PNMT) catalyzes the 2N-methylation (21.1 pmol/h per unit PNMT) of 9-methylnorharman, but not the 9N-methylation of 2-methylnorharmanium cation. LY134046, a selective inhibitor of phenylethanolamine N-methyltransferase, inhibits (IC 50 1.9 M) the 2N-methylation of 9-methylnorharman, a substrate for -carboline 2N-methyltransferase. Substrates of phenylethanolamine N-methyltransferase also inhibit -carboline 2N-methyltransferase activity in a concentration-dependent manner. -Carboline 2N-methyltransferase activity (43.7 pmol/h/mg protein) is present in human adrenal medulla, a tissue with high phenylethanolamine N-methyltransferase activity.
Neurotoxicology and Teratology, 2002
Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associate... more Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associated with aging, is characterized neurochemically by abnormal and profound loss of nigrostriatal dopamine (DA) neurons. A prominent current view is that the excessive degeneration of the dopaminergic system is the outcome of extended insults by environmental neurotoxins or endogenous neurotoxic factors in genetically vulnerable or susceptible individuals. Recent insights into the identities and mechanisms of potential neurotoxic species, which span pesticides, environmental contaminants including heterocyclic amines with b-carboline (bC) and isoquinoline (IQ) structures, endogenous DA metabolites or intermediates, neuromelanin, metals, and infectious agents, are presented. D (M.A. Collins).
Annals of The New York Academy of Sciences, 1992
Journal of Neurochemistry, 1992
Guinea pig brain S-adenosylmethionine (SAM)dependent N-methyltransferase activity toward physiolo... more Guinea pig brain S-adenosylmethionine (SAM)dependent N-methyltransferase activity toward physiologically relevant 0-carboline (BC) substrates was examined with reverse-phase HPLC and radiochemical detection. Representative BCs, norharman and harmine, were enzymatically methylated on the 2[B]-nitrogen by ['H]CH3-SAM in undialyzed homogenates to yield 2[P]-methylated BCs and subsequently on the 9[indole]-nitrogen to generate 2,9-dimethylated BC products. This may be the first account of mammalian indole N-methyl transfer. There was no HPLCevidence for 9-methyl BC or (from carbon methylation) 2,6-dimethyl BC products. Capillary gas chromatography-mass spectrometry analysis confirmed the structures of the 2,9-dimethyl and 2-methyl products of norharman. The 2[p]-and 9[indole]-N-methylation activities were mainly in the nuclear fractions and were negligible in undialyzed cytosol. This differs from the cytosolic SAM-dependent N-methylations reported with other azaheterocyclics, including 1,2,3,4-tetrahydro-BCs. The involvement of a single enzyme was suggested because the two N-methyl transfers with BC substrate had similar subcellular activity patterns, regional brain distributions, and K, and V,,, values. Sequential N-methylation of various BCs that have been observed in vivo may be a unique route to centrally retained N*,P-dirnethylated P-carbolinium ions. Because they resemble the synthetic parkinsonian toxicant, Nmethyl-4-phenylpyridinium, with respect to structure and neurotoxic activity, such "bioactivated" carbolinium ions could be endogenous causative factors in Parkinson's disease. Key Words: Azaheterocyclic N-methyltransferase-Neurotoxicant-N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-N-Methyl-4-phen ylpyridinium-Parkinson's disease. Matsubara K. et al. Novel S-adenosylmethioninedependent indole-N-methylation of P-carbolines in brain particulate fractions.
Journal of Neurochemistry, 2009
In several epidemiological studies, moderate ethanol consumption has been associated with reduced... more In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer’s dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer’s amyloid-β (Aβ) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early ‘sensors’ in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Aβ25–35 was undiminished by antagonism during the first 3 days of either adenosine A1 or Gαi/o protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Aβ neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR.
Neuroreport, 2000
... Collins, Michael A.; Neafsey, Edward J.; Zou, Jian-Yun. ... 4 Corresponding Author, Michael A... more ... Collins, Michael A.; Neafsey, Edward J.; Zou, Jian-Yun. ... 4 Corresponding Author, Michael A. Collins. ... cortical-hippocampal slice cultures and cerebellar granule cell cultures: Slice cultures were prepared from 8-to 10-day-old Sprague-Dawley rats (Zivic-Miller Labs, Portersville PA ...
Journal of Neurotrauma, 2009
Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entor... more Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol-dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can cause oxidative stress through non-edemic pathways has placed edema's role in question. We therefore studied three other diuretics and a related non-diuretic that, according to our oxygen radical antioxidant capacity (ORAC) assays or the literature, possess minimal antioxidant potential. Acetazolamide (ATZ), a carbonic anhydrase inhibitor=diuretic with negligible ORAC effectiveness and, interestingly, an aquaporin-4 (AQP4) water channel inhibitor, prevented alcohol-dependent tissue edema and neurodegeneration in HEC slice cultures. Likewise, in binge alcohol-intoxicated rats, ATZ suppressed brain edema while inhibiting neurodegeneration. Torasemide, a loop diuretic lacking furosemide's ORAC capability, also prevented alcohol-induced neurodamage in HEC slice cultures. However, bumetanide (BUM), a diuretic blocker of Na + -K + -2Cl À channels, and L-644, 711, a nondiuretic anion channel inhibitor-both lacking antioxidant capabilities as well as reportedly ineffective against alcohol-dependent brain damage in vivo-reduced neither alcohol-induced neurotoxicity nor (with BUM) edema in HEC slices. Because an AQP4 blocker (ATZ) was neuroprotective, AQP4 expression in the HEC slices was examined and found to be elevated by binge alcohol. The results further indicate that binge ethanol-induced brain edema=swelling, potentially associated with AQP4 upregulation, may be important in consequent neurodegeneration that could derive from neuroinflammatory processes, for example, membrane arachidonic acid mobilization and associated oxidative stress.
Alcoholism-clinical and Experimental Research, 1996
Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we exa... more Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we examined how two different NO synthase (NOS) inhibitors affected the extent of cerebrocortical and olfactory neuronal damage in a modified “binge intoxication” rat model (Collins et al., Alcohol Clin. Exp. Res. 20:284–292, 1996). Male rats intragastrically fed ethanol (6.5 to 12 g/kg/day) in nutrient solution three times daily for 4 days also received NG-nitro-L-arginine methyl ester by chronic intracerebroventricular infusion or 7-nitro-indazole by daily intraperitoneal injection; control rats were given nutrient solution only and/or vehicles. Blood ethanol levels did not differ among the ethanol-treated groups. The amount of ethanol-dependent neuronal degeneration in the entorhinal cortex, dentate gyrus, and olfactory bulb glomeruli—visualized with the de Olmos cupric silver stain and quantitatively assessed in the binge-intoxicated rats—was either unchanged or significantly increased by the NOS inhibitors. Although the efficacies of the inhibitors cannot be directly compared because various NOS forms were probably inhibited to differing extents, the results do not support the idea that endogenous NO is a neurotoxic mediator of ethanol's effects. Rather, NO may have a modest neuroprotectant role in this model of early brain damage induced by ethanol. In addition, the NOS that is localized histochemically as NADPH diaphorase was present primarily in regions and/or cells not damaged by binge ethanol treatment. Assuming that NADPH diaphorase represents most of the NO forming enzyme(s), this suggests a transcellular mechanism for NO. A further observation was that hippocampal CA pyramidal neuron degeneration was extensive in rats infused centrally with NG-nitro-L-arginine methyl ester.
Proceedings of The National Academy of Sciences, 1990
Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-meth... more Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP^+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated β-carbolines (2-MeβCs) and 2-methylated 3,4-dihydro-β-carbolines (2-MeDHβCs), which encompass the MPP^+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD^+-linked O_2 consumption (6-min preincubations) was as follows: MPP^+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methylharmalan >> 2-methylharman. Similar to MPP^+, 2-MeDHβC/2-MeβC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHβC/2-MeβC inhibitory time courses, which were unlike MPP^+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic β-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP^+ rather than 2-MeβCs. Succinate-supported respiration was also significantly blocked by 2-MeDHβCs/2-MeβCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD^+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHβCs/2-MeβCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MeβCs.
Alcoholism-clinical and Experimental Research, 1996
Severe, repetitive (“binge”) ethanol intoxication in adult rats (intragastric delivery 3 times da... more Severe, repetitive (“binge”) ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum—regions generally shown to have cell loss in long-term ethanol feeding models—but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.
Alcoholism-clinical and Experimental Research, 2004
This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fult... more This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were
Brain Research, 1986
In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patch... more In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patches of cortex devoted to particular movements. The location of major subdivisions such as the forelimb or hindlimb areas is somatotopic and is consistent from animal to animal, but the internal organization of the pattern of movements represented within major subdivisions varies significantly between animals. The motor cortex includes both agranular primary motor cortex (AgL) and, in addition, a significant amount of the bordering granular somatic sensory cortex (Gr(SI)), as well as the rostral portion of the taste sensory insular or claustrocortex (Cl). The rat frontal cortex also contains a second, rostral motor representation of the forelimb, trunk and hindlimb, which is somatotopically organized and may be the rat's supplementary motor area. Both of these motor representations give rise to direct corticospinal projections, some of which may make monosynaptic connections with cervical enlargement motoneurons. Medial to the primary motor cortex, in cytoarchitectonic field AgM, is what appears to be part of the rat's frontal eye fields, a region which also includes the vibrissae motor representation. The somatic motor cortical output organization pattern in the rat is remarkably similar to that seen in the primate, whose primary, supplementary and frontal eye field cortical motor regions have been extensively studied.
We previously reported anatomical plasticity in the adult motor cortex after a unilateral sensori... more We previously reported anatomical plasticity in the adult motor cortex after a unilateral sensorimotor cortex (SMC) lesion and treatment with monoclonal antibody (mAb) IN-1, which permits neurite outgrowth from the intact, opposite cortex into deafferented subcortical targets. This study was designed to investigate whether treatment with the mAb IN-1 after SMC lesion in the adult leads to functional reorganization of the intact, opposite motor cortex. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or control antibody, or no treatment. After a 6 week survival period, the intact, opposite forelimb motor cortex was explored using intracortical microstimulation to evoke forelimb movements. A dramatic increase in ipsilateral movements of the lesion-impaired forelimb was found in animals treated with mAb IN-1 compared with control animals. These results resembled our previous findings of cortical reorganization in the spared hemisphere after neonatal cortical lesion and without any additional treatment. These results show that, after adult cortical lesion, treatment with mAb IN-1 induces a functional reorganization of the intact, opposite motor cortex.
Experimental Neurology, 2006
Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulte... more Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulted in an apparent shift of the motor cortex map in the spared hemisphere, particularly of the hindlimb cortex. In view of such findings, the present study was initiated to determine if the visual cortex located both ipsilateral and contralateral to neonatal SMC, or contralateral to occipital cortical (OC) lesions, would show similar remodeling. Visual evoked potentials (VEPs) were used to map the visual cortex electrophysiologically. The results show an expansion of the visual cortex, in both the contralateral and ipsilateral hemisphere, into normally motor cortical areas in adult animals that had sustained unilateral neonatal unilateral SMC lesions. In contrast, similar changes were not seen within the spared visual cortex after unilateral occipital cortical lesions, suggesting that the shift in the visual map was specifically in response to the SMC lesion and was not a generalized response to neonatal cortical damage. Histological analysis showed a functional expansion in the rostral boundary of visual cortex with no corresponding cytoarchitectural alterations.
Experimental Neurology, 1979
Single-unit recordings were made in the entopeduncular nucleus of cats which had previously under... more Single-unit recordings were made in the entopeduncular nucleus of cats which had previously undergone ipsilateral caudate lesions. During penicillin-induced epileptiform discharge from the pericruciate cortex, the percentage of responsive entopeduncular neurons in animals with a lesion was less than 20%. In a previous study in intact cats and in control experiments in the present study the percentage of responsive entopeduncular cells was more than 75%. These results indicate that propagation of epileptic discharge through the basal ganglia depends on intact pathways from the cortex to the caudate and from the caudate to the entopeduncular nucleus.
Neurochemical Research, 1997
The activity of β-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methyl... more The activity of β-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated β-carbolinium compounds. We have hypothesized that these N-methylated β-carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain β-carboline-2-N-methyltransferase activity. The activity of β-carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5–9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 μM and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 μM and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals.
Journal of Neurochemistry, 2004
Endogenous or exogenous β-carboline (βC) derivatives structurally related to the selective dopami... more Endogenous or exogenous β-carboline (βC) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) may contribute to dopaminergic neurodegeneration in Parkinson's disease (PD). We addressed the importance of the dopamine transporter (DAT) for selective dopaminergic toxicity by testing the differential cytotoxicity and cellular uptake of 12 βCs in human embryonic kidney HEK-293 cells ectopically expressing the DAT gene. Cell death was measured using [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays, and uptake by a fluorescence-based uptake assay. All βCs and MPP+ showed general cytotoxicity in parental HEK-293 cells after 72 h with half-maximal toxic concentrations (TC50 values) in the upper micromolar range. Besides MPP+, only 2[N]-methylated compounds showed enhanced cytotoxicity in DAT expressing HEK-293 cells with 1.3- to 4.5-fold reduction of TC50 values compared with parental cell line. The rank order of selectivity was: MPP+ >> 2[N],9[N]-dimethyl-harminium > 2[N]-methyl-harminium > 2[N],9[N]-dimethyl-harmanium = 2[N]-methyl-norharmanium > 2[N]-methyl-harmanium > 2[N],9[N]-dimethyl-norharminium. Consistently, only 2[N]-methylated βCs were transported into the cell through the DAT with up to five times greater Km and 12–220 times smaller Vmax values compared with dopamine and MPP+. There was a weak relation of DAT-mediated selectivity with the affinity of βCs at the DAT (Km), but not with Vmax. Our data suggest that DAT-mediated cellular uptake of 2[N]-methylated βCs represents a potential mechanism for selective toxicity towards dopaminergic neurons and may be relevant for the pathogenesis of Parkinson's disease.
Neuroreport, 2004
ABSTRACT Consumers of moderate amounts of ethanol have a lower risk of Alzheimer's dement... more ABSTRACT Consumers of moderate amounts of ethanol have a lower risk of Alzheimer's dementia than do abstainers. In Alzheimer's disease the brain contains many extracellular plaques composed of amyloid-beta (Abeta), a neurotoxic protein linked to pathogenesis of the disease. Here we report that moderate ethanol preconditioning (20-30 mM for 6 days) of organotypic hippocampal-entorhinal slice cultures prevents Abeta-induced neurotoxicity and apoptosis as measured by media lactate dehydrogenase levels and staining with propidium iodide and Hoechst 33342. With Abeta, as with our previous studies of the neurotoxic HIV-I protein gp120, moderate ethanol preconditioning may interfere with various glial-mediated neurotoxic responses in the slices to A. In addition, we found that moderate ethanol preconditioning causes an almost 3-fold increase in brain levels of heat shock protein 70 (hsp70), a protective molecular chaperone. Our results suggest possible molecular mechanisms underlying the protective effect of moderate drinking against Alzheimer's dementia.
Neurobiology of Disease, 2000
Enzymatic -carboline N-methyltransferase activities generate N-methylated -carbolinium cations ... more Enzymatic -carboline N-methyltransferase activities generate N-methylated -carbolinium cations that are analogs of the parkinsonian-producing neurotoxin MPP؉. We measured -carboline-2Nmethyltransferase and -carboline-9N-methyltransferase activities in the supernatant and particulate fractions from postmortem human brains. These N-methyltransferase activities were assessed in the substantia nigra, putamen, and frontal cortex from control and Parkinson's disease cases. No significant differences were measured in any brain region in particulate and supernatant fraction -carboline 2N-methyltransferase activity or particulate fraction -carboline 9N-methyltransferase activity. Likewise, supernatant fraction -carboline 9N-methyltransferase activity was similar in the putamen and substantia nigra from Parkinson's disease and control cases. Unexpectedly, supernatant fraction -carboline 9N-methyltransferase activity was increased fourfold in Parkinson's disease frontal cortex (P < 0.05), suggesting that -carboline N-methylation may play a role in Parkinson's disease.
Neurochemical Research, 2009
Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether p... more Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether phospholipase A2 (PLA2) activity is involved in binge alcohol (ethanol)-induced neurodegeneration, and whether docosahexaenoic acid (DHA; 22:6n-3), a fish oil-enriched fatty acid that is anti-inflammatory in brain damage models, is neuroprotective. Assessed with propidium iodide and lactate dehydrogenase (LDH) leakage, neurodamage from ethanol (6 days 100 mM ethanol with four withdrawal periods) was prevented by the PLA2 pan-inhibitor, mepacrine. Also, ethanol-dependent neurodegeneration—particularly in the entorhinal region—was significantly ameliorated by DHA supplementation (25 μM); however, adrenic acid, a 22:4n-6 analog, was ineffective. Consistent with PLA2 activation, [3H] liberation was approximately fivefold greater in [3H]arachidonic acid-preloaded HEC slice cultures during ethanol withdrawal compared to controls, and DHA supplementation suppressed [3H] release to control levels. DHA might antagonize PLA2 activity directly or suppress upstream activators (e.g., oxidative stress); however, other DHA mechanisms could be important in subdueing ethanol-induced PLA2-dependent and independent neuroinflammatory processes.
Neurochemistry International, 2002
Mammalian brain has a -carboline 2N-methyltransferase activity that converts -carbolines, such ... more Mammalian brain has a -carboline 2N-methyltransferase activity that converts -carbolines, such as norharman and harman, into 2N-methylated -carbolinium cations, which are structural and functional analogs of the Parkinsonian-inducing toxin 1-methyl-4phenylpyridinium cation (MPP + ). The identity and physiological function of this -carboline 2N-methylation activity was previously unknown. We report pharmacological and biochemical evidence that phenylethanolamine N-methyltransferase (EC 2.1.1.28) has -carboline 2N-methyltransferase activity. Specifically, purified phenylethanolamine N-methyltransferase (PNMT) catalyzes the 2N-methylation (21.1 pmol/h per unit PNMT) of 9-methylnorharman, but not the 9N-methylation of 2-methylnorharmanium cation. LY134046, a selective inhibitor of phenylethanolamine N-methyltransferase, inhibits (IC 50 1.9 M) the 2N-methylation of 9-methylnorharman, a substrate for -carboline 2N-methyltransferase. Substrates of phenylethanolamine N-methyltransferase also inhibit -carboline 2N-methyltransferase activity in a concentration-dependent manner. -Carboline 2N-methyltransferase activity (43.7 pmol/h/mg protein) is present in human adrenal medulla, a tissue with high phenylethanolamine N-methyltransferase activity.
Neurotoxicology and Teratology, 2002
Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associate... more Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associated with aging, is characterized neurochemically by abnormal and profound loss of nigrostriatal dopamine (DA) neurons. A prominent current view is that the excessive degeneration of the dopaminergic system is the outcome of extended insults by environmental neurotoxins or endogenous neurotoxic factors in genetically vulnerable or susceptible individuals. Recent insights into the identities and mechanisms of potential neurotoxic species, which span pesticides, environmental contaminants including heterocyclic amines with b-carboline (bC) and isoquinoline (IQ) structures, endogenous DA metabolites or intermediates, neuromelanin, metals, and infectious agents, are presented. D (M.A. Collins).
Annals of The New York Academy of Sciences, 1992
Journal of Neurochemistry, 1992
Guinea pig brain S-adenosylmethionine (SAM)dependent N-methyltransferase activity toward physiolo... more Guinea pig brain S-adenosylmethionine (SAM)dependent N-methyltransferase activity toward physiologically relevant 0-carboline (BC) substrates was examined with reverse-phase HPLC and radiochemical detection. Representative BCs, norharman and harmine, were enzymatically methylated on the 2[B]-nitrogen by ['H]CH3-SAM in undialyzed homogenates to yield 2[P]-methylated BCs and subsequently on the 9[indole]-nitrogen to generate 2,9-dimethylated BC products. This may be the first account of mammalian indole N-methyl transfer. There was no HPLCevidence for 9-methyl BC or (from carbon methylation) 2,6-dimethyl BC products. Capillary gas chromatography-mass spectrometry analysis confirmed the structures of the 2,9-dimethyl and 2-methyl products of norharman. The 2[p]-and 9[indole]-N-methylation activities were mainly in the nuclear fractions and were negligible in undialyzed cytosol. This differs from the cytosolic SAM-dependent N-methylations reported with other azaheterocyclics, including 1,2,3,4-tetrahydro-BCs. The involvement of a single enzyme was suggested because the two N-methyl transfers with BC substrate had similar subcellular activity patterns, regional brain distributions, and K, and V,,, values. Sequential N-methylation of various BCs that have been observed in vivo may be a unique route to centrally retained N*,P-dirnethylated P-carbolinium ions. Because they resemble the synthetic parkinsonian toxicant, Nmethyl-4-phenylpyridinium, with respect to structure and neurotoxic activity, such "bioactivated" carbolinium ions could be endogenous causative factors in Parkinson's disease. Key Words: Azaheterocyclic N-methyltransferase-Neurotoxicant-N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-N-Methyl-4-phen ylpyridinium-Parkinson's disease. Matsubara K. et al. Novel S-adenosylmethioninedependent indole-N-methylation of P-carbolines in brain particulate fractions.
Journal of Neurochemistry, 2009
In several epidemiological studies, moderate ethanol consumption has been associated with reduced... more In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer’s dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer’s amyloid-β (Aβ) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early ‘sensors’ in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Aβ25–35 was undiminished by antagonism during the first 3 days of either adenosine A1 or Gαi/o protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Aβ neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR.
Neuroreport, 2000
... Collins, Michael A.; Neafsey, Edward J.; Zou, Jian-Yun. ... 4 Corresponding Author, Michael A... more ... Collins, Michael A.; Neafsey, Edward J.; Zou, Jian-Yun. ... 4 Corresponding Author, Michael A. Collins. ... cortical-hippocampal slice cultures and cerebellar granule cell cultures: Slice cultures were prepared from 8-to 10-day-old Sprague-Dawley rats (Zivic-Miller Labs, Portersville PA ...
Journal of Neurotrauma, 2009
Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entor... more Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol-dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can cause oxidative stress through non-edemic pathways has placed edema's role in question. We therefore studied three other diuretics and a related non-diuretic that, according to our oxygen radical antioxidant capacity (ORAC) assays or the literature, possess minimal antioxidant potential. Acetazolamide (ATZ), a carbonic anhydrase inhibitor=diuretic with negligible ORAC effectiveness and, interestingly, an aquaporin-4 (AQP4) water channel inhibitor, prevented alcohol-dependent tissue edema and neurodegeneration in HEC slice cultures. Likewise, in binge alcohol-intoxicated rats, ATZ suppressed brain edema while inhibiting neurodegeneration. Torasemide, a loop diuretic lacking furosemide's ORAC capability, also prevented alcohol-induced neurodamage in HEC slice cultures. However, bumetanide (BUM), a diuretic blocker of Na + -K + -2Cl À channels, and L-644, 711, a nondiuretic anion channel inhibitor-both lacking antioxidant capabilities as well as reportedly ineffective against alcohol-dependent brain damage in vivo-reduced neither alcohol-induced neurotoxicity nor (with BUM) edema in HEC slices. Because an AQP4 blocker (ATZ) was neuroprotective, AQP4 expression in the HEC slices was examined and found to be elevated by binge alcohol. The results further indicate that binge ethanol-induced brain edema=swelling, potentially associated with AQP4 upregulation, may be important in consequent neurodegeneration that could derive from neuroinflammatory processes, for example, membrane arachidonic acid mobilization and associated oxidative stress.
Alcoholism-clinical and Experimental Research, 1996
Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we exa... more Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we examined how two different NO synthase (NOS) inhibitors affected the extent of cerebrocortical and olfactory neuronal damage in a modified “binge intoxication” rat model (Collins et al., Alcohol Clin. Exp. Res. 20:284–292, 1996). Male rats intragastrically fed ethanol (6.5 to 12 g/kg/day) in nutrient solution three times daily for 4 days also received NG-nitro-L-arginine methyl ester by chronic intracerebroventricular infusion or 7-nitro-indazole by daily intraperitoneal injection; control rats were given nutrient solution only and/or vehicles. Blood ethanol levels did not differ among the ethanol-treated groups. The amount of ethanol-dependent neuronal degeneration in the entorhinal cortex, dentate gyrus, and olfactory bulb glomeruli—visualized with the de Olmos cupric silver stain and quantitatively assessed in the binge-intoxicated rats—was either unchanged or significantly increased by the NOS inhibitors. Although the efficacies of the inhibitors cannot be directly compared because various NOS forms were probably inhibited to differing extents, the results do not support the idea that endogenous NO is a neurotoxic mediator of ethanol's effects. Rather, NO may have a modest neuroprotectant role in this model of early brain damage induced by ethanol. In addition, the NOS that is localized histochemically as NADPH diaphorase was present primarily in regions and/or cells not damaged by binge ethanol treatment. Assuming that NADPH diaphorase represents most of the NO forming enzyme(s), this suggests a transcellular mechanism for NO. A further observation was that hippocampal CA pyramidal neuron degeneration was extensive in rats infused centrally with NG-nitro-L-arginine methyl ester.
Proceedings of The National Academy of Sciences, 1990
Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-meth... more Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP^+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated β-carbolines (2-MeβCs) and 2-methylated 3,4-dihydro-β-carbolines (2-MeDHβCs), which encompass the MPP^+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD^+-linked O_2 consumption (6-min preincubations) was as follows: MPP^+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methylharmalan >> 2-methylharman. Similar to MPP^+, 2-MeDHβC/2-MeβC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHβC/2-MeβC inhibitory time courses, which were unlike MPP^+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic β-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP^+ rather than 2-MeβCs. Succinate-supported respiration was also significantly blocked by 2-MeDHβCs/2-MeβCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD^+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHβCs/2-MeβCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MeβCs.
Alcoholism-clinical and Experimental Research, 1996
Severe, repetitive (“binge”) ethanol intoxication in adult rats (intragastric delivery 3 times da... more Severe, repetitive (“binge”) ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum—regions generally shown to have cell loss in long-term ethanol feeding models—but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.
Alcoholism-clinical and Experimental Research, 2004
This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fult... more This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were