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    • Ac-DEVD-pNA By association a possible mechanism which may un

    2021-09-11

    By association, a possible mechanism which may underlie the progression of seizures is long-term potentiation (LTP). Indeed, LTP shares many common mechanisms with seizures activity both anatomically and physiologically, and has been implicated as a mechanism of acute epileptogenesis (Wasterlain et al., 1999). Galanin reportedly was an effective inhibitor of LTP both in vivo and in vitro (Coumis and Davies, 2002, Mazarati et al., 2000, O’Meara et al., 2000, Sakurai et al., 1996).
    Galanin is an inhibitor of seizure activity SE consists of two phases – initiation, which strongly depends on the initial epileptogenic stimulus (which may include electrical stimulation of perforant path, activation of cholinergic transmission by pilocarpine, or activation of AMPA/kainate receptors by kainic acid), and maintenance, which does not depend on the initial epileptogenic stimulation (Mazarati and Wasterlain, 1999, Wasterlain et al., 2000). The mechanisms of the transition from the Ac-DEVD-pNA to the maintenance phase are complex and are far from being understood; however, it is agreed that this transition, as well as self-perpetuation of seizures once they have been established depend on the activation of N-methyl-d-aspartate receptors (Wasterlain et al., 2000). Mazarati et al. (1998) reported that SE leads to the profound depletion of galaninergic innervation of the dentate gyrus as soon as after 3 h of self-sustaining seizures. Our recent observations (personal unpublished data, Fig. 1(c)) found that such depletion occurs even earlier – after only 30 min of seizures, i.e., roughly coincides with the transition from the initiation to the maintenance phase of SE. Furthermore, intrahippocampal administration of GalR agonists during this transition time rapidly and irreversibly aborted seizures (Mazarati et al., 1998, Mazarati and Wasterlain, 2002). Taken together these data suggested that galanin may indeed act as an anticonvulsant peptide, and that fatigue of galaninergic innervation of the hippocampus may contribute to the progression of seizures. These studies, however, did not prove that endogenous galanin counteracted seizure activity. Such evidence came from the experiments which used galanin mutant animals (Fig. 2(a)). Mice with the functional disruption of galanin gene showed higher seizure susceptibility than their wild type littermates, evident as shorter time needed to induce seizures and higher severity of the convulsions once those were induced (Mazarati et al., 2000). In contrast, mice which overexpressed galanin under dopamine beta hydroxylase promoter, i.e., in catecholaminergic pathways, showed enhanced resistance to seizure induction (Mazarati et al., 2000). Overexpression of galanin under platelet-derived growth factor B promoter (i.e., not confined to catecholaminergic system) inhibited the progression of kindled seizures, and increased after discharge threshold upon hippocampal stimulation (Kokaia et al., 2001), thus confirming initial anti-kindling action of galanin (Mazarati et al., 1992) and expanding anticonvulsant effectiveness of the peptide beyond SE. An elegant approach further exploring anticonvulsant role of galanin was applied in the studies which used adeno-associated virus (AAV) vector carrying galanin gene, to transfect neurons in rats in vivo. Haberman et al. (2003) cloned a coding sequence of galanin into the AAV vector, which also contained fibronectin secretory signal sequence (FIB), to ensure not only expression but also active secretion of galanin into the extracellular space. In vivo injection of AAV-FIB-GAL vector into the inferior colliculus of the rat significantly attenuated seizures induced by focal electrical stimulation of this brain area. In contrast, administration of AAV-GAL vector, which led to the overexpression of galanin, but not to the increased secretion of the peptide, had no anticonvulsant effects (Haberman et al., 2003). This finding was partly disputed by Lin et al. (2003), who found that just overexpression of galanin induced by AAV-Neuron Specific Enolase (NSE)-GAL vector in the rat dentate gyrus neurons (both hilar interneurons and dentate granule cells) was sufficient to attenuate the severity of focal convulsions induced by intrahippocampal administration of kainic acid. The result suggested that the secretion of galanin which was presumably induced by seizures (Hokfelt et al., 1987) from neurons expressing galanin de novo, was sufficient to inhibit focal epileptic activity. In the light of these data, it is worth mentioning that seizures themselves led to the expression of galanin in the hippocampus, presumably in hilar interneurons (Mazarati et al., 1998, Koh et al., 2004). Such de novo expression of hippocampal galanin may represent a mechanism purposed to compensate for the discussed above fatigue of galaninergic innervation resulting from seizures, and to form an intrinsic hippocampal galanin inhibitory circuit.