3-Acetylpyridine Produces Age-Dependent Excitotoxic Lesions in Rat Striatum

Schulz, Jörg B.; Henshaw, D. Ross; Jenkins, Bruce G.; Ferrante, Robert J.; Kowall, Neil W.; Rosen, Bruce R.; Beal, M. Flint

doi:10.1038/jcbfm.1994.134

Cited by 36 publications

(7 citation statements)

References 21 publications

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“…Thus, in rat studies, LTG attenuated lesion volume with striatal injections of the excitotoxin 3-acetylpyridine, 90 and hippocampal slice perfusion with 0.1-mM LTG and 1.2-to 1.6-mM FBM (but not placebo) decreased irreversible disappearance of the CA1 electrical responses induced by kainate (but not by NMDA or a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). 91 LTG pretreatment reduced hippocampal neuronal loss but only tended to protect from seizures in the kainate-induced multifocal status epilepticus rat model of intractable complex partial seizures and neurotoxicity.…”

Section: Putative Neuroprotective Effectsmentioning

confidence: 88%

Potential Mechanisms of Action of Lamotrigine in the Treatment of Bipolar Disorders

Ketter¹,

Manji²,

Post³

2003

Journal of Clinical Psychopharmacology

113

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Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile.

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Section: Putative Neuroprotective Effectsmentioning

confidence: 88%

Potential Mechanisms of Action of Lamotrigine in the Treatment of Bipolar Disorders

Ketter¹,

Manji²,

Post³

2003

Journal of Clinical Psychopharmacology

113

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“…3-Acetylpyridine is a niacinamide antagonist that impairs energy metabolism due to its substitution for niacinamide in NAD(P) formation and has potent neurotoxic properties in vitro and in vivo (Sethy et al, 1997). 3-Acetylpyridine neurotoxicity also has an NMDA receptor excitotoxic component, and the NMDA antagonist MK-801 can diminish its toxicity (Schulz et al, 1994). The GABA inverse agonist PNU-101017 demonstrated a partial but significant neuroprotective effect 8 h after administration of 3-acetylpyridine in rats (Sethy et al, 1997).…”

Section: Benzodiazepine Receptor and 'Inverse' Agonistsmentioning

confidence: 98%

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.

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“…In addition, mitochondrial dysfunction will enhance the production of reactive oxygen species (ROS), which will also contribute to neuronal damage (Murphy et al, 1999). Substantial evidence indicates that mitochondrial toxins induce neuronal damage through an excitotoxic‐mediated mechanism (Storey et al, 1992; Beal et al, 1993; Grenee et al, 1993; Brouillet et al, 1994; Schulz et al, 1994) and potentiate glutamate neurotoxicity both in vivo and in vitro (Novelli et al, 1988; Greene and Greenamyre, 1995; Cebers et al, 1998; Greene et al, 1998; Sánchez‐Carbente and Massieu, 1999). All these studies favor the hypothesis of a close and complex interrelation between mitochondrial energy metabolism and glutamate excitotoxicity (Henneberry, 1989).…”

Section: Introductionmentioning

confidence: 99%

Strategies for neuroprotection against L‐trans‐2,4‐pyrrolidine dicarboxylate‐induced neuronal damage during energy impairment in vitro

García

Massieu

2001

J of Neuroscience Research

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Increased levels of extracellular excitatory amino acids and failure of energy metabolism are two conditions associated with brain ischemia. In the present study we have combined the simultaneous inhibition of glutamate uptake and mitochondrial electron transport chain to simulate neuronal damage associated with brain ischemia. Results show that cerebellar granule neurons are not vulnerable to transient glutamate uptake inhibition by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) despite the increase in the extracellular concentration of glutamate, unless they are simultaneously exposed to the mitochondrial toxins 3-nitropropionic acid (3-NP) or sodium azide. Cell damage was assessed by light microscopy observation, by reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and by the fluorescent markers for live and dead cells, calcein and ethidium homodimer, respectively. The protective effect of alternative energy substrates, such as pyruvate, acetoacetate, and beta-hydroxybutyrate against PDC-induced neuronal death during 3-NP exposure was studied and compared to the effects of the antioxidant vitamin E, the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN), voltage-dependent calcium channel antagonists, and glutamate receptor antagonists. Results show that neuronal damage can be efficiently prevented in the presence of pyruvate and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, whereas the non-NMDA receptor antagonist NBQX, acetoacetate, vitamin E, and PBN showed partial protection. In contrast, beta-hydroxybutyrate and voltage-dependent calcium channels blockers did not show any protective effect at the concentrations tested.

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3-Acetylpyridine Produces Age-Dependent Excitotoxic Lesions in Rat Striatum

Cited by 36 publications

References 21 publications

Potential Mechanisms of Action of Lamotrigine in the Treatment of Bipolar Disorders

Potential Mechanisms of Action of Lamotrigine in the Treatment of Bipolar Disorders

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Strategies for neuroprotection against L‐trans‐2,4‐pyrrolidine dicarboxylate‐induced neuronal damage during energy impairment in vitro

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