Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 22

The GABA hypothesis of epilepsy implies that a reduction of GABA-ergic inhibition results in epilepsy whereas an enhancement of GABA-ergic inhibition results in an anti-epileptic effect (Wong and Watkins, 1982; De Deyn and Macdonald, 1990; De Deyn et al., 1990). Inhibitory postsynaptic potentials (IPSPs) gradually decrease in amplitude during repetitive activation of cortical circuits. This phenomenon might be caused by decreases in GABA release from terminals, desensitization of GABA receptors that are coupled to increases in Cl− conductance or alterations in the ionic gradient because of intracellular accumulation of Cl− (Wong and Watkins, 1982). In case of intracellular accumulation of Cl−, passive redistribution is ineffective. Moreover, Cl−–K+ co-transport becomes less effective during seizures as it depends on the K+ gradient. As Cl−–K+ co-transport depends on metabolic processes, its effectiveness may be affected by hypoxia or ischaemia as well. These mechanisms may play a critical role in ictogenesis and interictal–ictal transition. Several studies have shown that GABA is involved in pathophysiology of epilepsy in both animal models and patients suffering from epilepsy. GABA levels and glutamic acid decarboxylase (GAD) activity were shown to be reduced in epileptic foci surgically excised from patients with intractable epilepsy and in CSF of patients with certain types of epilepsy (De Deyn et al., 1990).

A reduction of 3H–GABA binding has been reported in human brain tissue from epileptic patients whereas PET studies demonstrated reduced benzodiazepine receptor binding in human epileptic foci (Savic et al., 1996). The degree of benzodiazepine receptor reduction showed a positive correlation with seizure frequency. The GABA receptor complex is involved in various animal models of epilepsy as well. Low CSF levels of GABA were revealed in dogs with epilepsy (Loscher and Schwartz-Porsche, 1986). Reduced GAD levels were revealed in the substantia nigra of amygdala-kindled rats (Loscher and Schwark, 1985). Significant alterations in GABA and benzodiazepine binding have been shown in the substantia nigra of genetically seizure-prone gerbils (Olsen et al., 1985). Mice with a genetic susceptibility to audiogenic seizures have a lower number of GABA receptors than animals of the same strain that are not seizure prone (Horton et al., 1982). Several endogenous (guanidino compounds) and exogenous (e.g. bicuculline, picrotoxin, penicillin, pilocarpine, pentylenetetrazol) convulsants inhibit GABA-ergic transmission through inhibition of GABA synthesis or through interaction with distinct sites at the postsynaptic GABAA receptor (De Deyn and Macdonald, 1990; D’Hooge et al., 1996). Convulsant agents that block synaptic GABA-mediated inhibition, amplify the dendritic spike-generating mechanism that involves Ca2+ (Dichter and Ayala, 1987; Fisher, 1989). Synaptic inputs are thought to trigger and synchronize this process throughout a population of cells, which then might result in an epileptic seizure. Several AEMs are GABA analogues, block GABA metabolism or facilitate postsynaptic effects of GABA. However, a study evaluating dose-dependent behavioural effects of single doses of vigabatrin in audiogenic sensitive rats, suggests that the anti-epileptic properties of vigabatrin not only depend on GABA-ergic neurotransmission but might also be explained by decreased central nervous system levels of excitatory amino acids or increased glycine concentrations (Engelborghs et al., 1998b).