Delayed Transneuronal Death of Substantia Nigra Neurons Prevented by γ-Aminobutyric Acid Agonist

Saji, Makoto; Reis, Donald J.

doi:10.1126/science.3798095

Cited by 213 publications

(86 citation statements)

References 23 publications

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“…[35][36][37] In agreement with this hypothesis, it has been shown that the GABA A agonist muscimol inhibits N-methyl-D-aspartate-induced neurotoxicity in primary cell cultures. 38 Conversely, less clear is the protective role induced by activation of GABA B receptors.…”

Section: Discussionmentioning

confidence: 54%

Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia

Costa

Leone

Saulle

et al. 2004

Stroke

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Background and Purpose-The possible neuroprotective effect of endogenous ␥-aminobutyric acid (GABA) on the irreversible electrophysiological changes induced by in vitro ischemia on striatal neurons was investigated. In particular, the aim of the study was the characterization of the neuroprotective action of 2 antiepileptic drugs increasing GABAergic transmission such as tiagabine, a GABA transporter inhibitor, and vigabatrin, an irreversible inhibitor of GABA transaminase. Methods-Extracellular field potential recordings were obtained from rat corticostriatal slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose was omitted and oxygen was replaced with N 2 . Results-An irreversible loss of the field potentials recorded from striatal neurons was observed after 10 minutes of ischemia in control solution. Conversely, tiagabine and vigabatrin partially prevented the ischemia-induced field potential loss. Surprisingly, both GABA A and GABA B receptor antagonists blocked these effects. Accordingly, neuroprotection could be obtained only when GABA A and GABA B receptor agonists were coapplied, but not when a single agonist was given in isolation. Key Words: anticonvulsants Ⅲ corpus striatum Ⅲ electrophysiology Ⅲ ischemia Ⅲ receptors, GABA C ombined oxygen and glucose deprivation is a wellestablished in vitro model of ischemia for electrophysiological studies. 1-3 The striatum and hippocampus are particularly vulnerable to ischemic insult, and neuronal damage is expressed as an alteration of both intrinsic membrane properties and synaptic transmission of the recorded cells. 4 -6 A large body of experimental work has been devoted to explore the neuroprotective efficacy of drugs blocking glutamate neurotransmission in animal models of cerebral ischemia. 3,[7][8][9][10][11] More recently, however, attention has been also focused on ␥-aminobutyric acid (GABA) changes during ischemia and on possible neuroprotective effects of GABAergic drugs. [12][13][14][15] Although a number of studies have suggested that increasing GABAergic synaptic transmission might display neuroprotective effects against brain ischemia, 16 -20 the exact mechanisms underlying these effects have yet to be elucidated. Conclusions-AntiepilepticIncreasing GABA function might represent a beneficial therapeutic approach to acute ischemia for different reasons. 13,19,20 First, endogenous GABA synthesis and release with consequent reduction in GABAergic transmission are decreased after an ischemic insult. Second, since glutamatergic and GABAergic transmissions work by each counterbalancing the function of the other, enhancing GABAergic activity should balance excessive glutamatergic excitation, which is the pivotal event leading to cell death.The aim of the present study is to characterize the electrophysiological effects of 2 currently used GABAergic antiepileptic drugs, tiagabine and vigabatrin, and to examine the cellular sites at which they act by using recordings from rat cortico...

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Section: Discussionmentioning

confidence: 54%

Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia

Costa

Leone

Saulle

et al. 2004

Stroke

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“…24 - 25 Muscimol appears to block transneuronal degeneration after other insults as well. 19 The GABA-B agonist baclofen was not protective in a previous study of radial arm maze learning after bilateral forebrain ischemia, further suggesting that the protection of GABA is a postsynaptic effect. 53 This report also contains a new, quantitative method for measuring the effect of an insult, such as ischemia, on brain compartment volumes.…”

Section: Discussionmentioning

confidence: 95%

Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist.

Lyden

Lonzo

1994

Stroke

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The excitotoxic effects of glutamate can be blocked almost completely with gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in cell culture, tissue slices, and in some animal models. After stroke in rats, we showed previously that an agonist of GABA, muscimol, was as neuroprotective as MK-801, an antagonist of glutamate. To obtain further neuroprotection and to avoid the side effects associated with high doses of MK-801, we wanted to assess the efficacy of the two agents in combination. Treatment was administered 5 minutes after embolic cerebral ischemia in Sprague-Dawley rats. The subjects were rated using a neurological evaluation 48 hours later. Visual-spatial learning was measured 8 to 10 weeks after stroke, after which we measured the volume of each cerebral hemisphere and several large cerebral compartments. Treatment groups included saline (n = 27), MK-801 1.0 mg/kg (n = 23), muscimol 1.0 mg/kg (n = 17), and both agents together using a dose of 0.5 mg/kg each (n = 25). A probit analysis of the neurological ratings revealed a protective effect of muscimol used alone (MK-801 potency ratio, 2.0; P = NS; muscimol potency ratio, 4.0; P < .05) and a protective effect of the combination (potency ratio, 5.0; P < .05). Focal ischemia caused a moderate to severe delay in the acquisition of visual-spatial information, which was completely eliminated by the combination treatment but only partially ameliorated with MK-801 or muscimol alone. Ischemia reduced the cerebral hemisphere volume from 0.42 mm3 to 0.34 mm3 (P < .0001), the volume density of cortex from 22% to 17% of total cerebral volume (P < .01), and that of hippocampus from 4.3% to 3.0% (P < .05). Only the combination was neuroprotective, as measured by the ratio of the lesioned to the contralateral hemisphere volume (P = .013). The combination treatment and MK-801 protected the hemisphere volume, the cortex, and the hippocampus and reduced the size of visible infarction. Combination therapy, using a glutamate antagonist and a GABA-A agonist, appeared to protect the brain and ameliorate a defect in learning behavior after stroke. The combination may have been more effective than either agent used alone, although further study of higher doses is needed.

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“…The data from our experiments suggest that the neurons that express higher levels of c-fos may be the ones that survive the injury. Recent studies have suggested the importance of feedforward neuronal degeneration that may be produced as a result of deafferenting lesions in reciprocally connected pathways such as the nigrostriatal system (Saji and Reis, 1987;Pasinetti et al, 199 1). The delayed transneuronal cell death in the SNr, similar to that observed in the SNc, is protracted, taking up to 21 d to have its maximal effect (Saji and Reis, 1987).…”

Section: Discussionmentioning

confidence: 99%

Differential spatial and temporal gene expression in response to axotomy and deafferentation following transection of the medial forebrain bundle

et al. 1993

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Alterations in the levels of neurotransmitter biosynthetic enzymes are a concomitant of many neurodegenerative disorders. In order to elucidate potential mechanisms for longterm alterations in biosynthetic enzyme gene products in response to neuronal injury, an acute axotomy/deafferentation model was employed. A unilateral microknife transection of the medial forebrain bundle (MFB) axotomizes and/or deafferents phenotypically identified neuronal populations important in the function of the basal ganglia. Semi-quantitative in situ hybridization and immunohistochemical analysis demonstrated that the products of the immediate-early gene c-fos were induced postaxotomy in the noradrenergic neurons of the locus ceruleus (LC), but not in the dopaminergic neurons of the substantia nigra pars compacta (SNc). Analysis of the levels of mRNA, protein, and activity for tyrosine hydroxylase demonstrated that the LC neurons survive the injury while the SNc neurons degenerate. After MFB transection, Fos protein also was induced in the corpus striatum within 1 hr, first in large, putatively cholinergic neuronal populations followed at 3 hr by the small, putatively GABAergic neurons. The substantia nigra pars reticulata and the subthalamic nucleus neuronal populations, deafferented by the MFB transection, also exhibited Fos induction beginning at 3 hr. The data suggest that expression of Fos in a neuronal population is correlative with respect to cell survival following either axotomy or deafferentation. Whether Fos induction following injury is either a necessary mechanism of cell survival or merely a marker of increased neuronal activity requires further investigation.

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Delayed Transneuronal Death of Substantia Nigra Neurons Prevented by γ-Aminobutyric Acid Agonist

Cited by 213 publications

References 23 publications

Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia

Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia

Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist.

Differential spatial and temporal gene expression in response to axotomy and deafferentation following transection of the medial forebrain bundle

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Delayed Transneuronal Death of Substantia Nigra Neurons Prevented by γ-Aminobutyric Acid Agonist

Cited by 213 publications

References 23 publications

Coactivation of GABA A and GABA B Receptor Results in Neuroprotection During In Vitro Ischemia

Coactivation of GABA A and GABA B Receptor Results in Neuroprotection During In Vitro Ischemia

Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist.

Differential spatial and temporal gene expression in response to axotomy and deafferentation following transection of the medial forebrain bundle

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Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia

Coactivation of GABA _A and GABA _B Receptor Results in Neuroprotection During In Vitro Ischemia