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

Abstract

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...

La atorvastatina protege las neuronas GABAérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

“…The findings in this study were also consistent with our previous observations of increased neuronal death and decreased Bcl-2 levels in the SNr following an ischemic event (20). In addition, our data show that post-ischemia ATV treatment increases GAD 65/67 immunoreactivity, which may suggest a potential mechanism for the observed neuroprotective effects by enhancing GABAergic transmission, which is consistent with other studies demonstrating that inducing certain inhibitory conditions can be used to control cell death following ischemia (28,(30)(31)(32)(33).…”

“…It is important to emphasize that during an ischemic stroke, glutamatergic activity increases, which decreases the endogenous synthesis and release of GABA, leading to reduced GABAergic transmission. As glutamatergic and GABAergic transmissions have antagonistic effects, increases in GABAergic activity in an ischemic setting can compensate for the excess glutamatergic signaling, leading to decreased cell death; conversely, decreased GABAergic signaling in this setting promotes cell death (28,29). The findings in this study were also consistent with our previous observations of increased neuronal death and decreased Bcl-2 levels in the SNr following an ischemic event (20).…”

Painted Turtle Cortex is Resistant to anin VitroMimic of the Ischemic Mammalian Penumbra

“…This represents a significant systemic advantage relative to ischemic stress in mammals; however, turtles are also considerably more tolerant to ischemic stress and survive > 1 hour after cardiac excision at 221C (Belkin, 1968). Furthermore, mimicking the turtle's endogenous cell-level neuroprotective mechanisms (inhibiting glutamatergic activity-channel arrest, or enhancing GABAergic activity-spike arrest) is neuroprotective against ischemic or hypoxic injury in mammalian brain (Arundine and Tymianski, 2004;Costa et al, 2004). Therefore, the ability of anoxia-tolerant turtle brain to withstand ischemic stress is of interest to better understand how neuroprotective adaptations to lowoxygen environments may provide protection against more complex ischemic challenges.…”

Tiagabine May Reduce Bruxism and Associated Temporomandibular Joint Pain

“…Tiagabine, in addition to its approved indication, is being explored off-label for the treatment of muscle spasm and neuropathic pain, 21 generalized anxiety disorder, 22 and posttraumatic stress disorder 23 ; for postischemic neuron protection 24 ; for the treatment of postencephalitis impulse dyscontrol 25 ; and for other uses.…”