The pilocarpine model is based on status epilepticus (SE) induction in rodents to mimictemporal lobe epilepsy as observed in humans. Depending on SE duration, widespreaddamage is observed in hippocampal or extrahippocampal regions leading to gliosis andreorganization of neuronal circuits [1]. Glial cells can play a role in modulating the lesionoutcome through the release of neurotrophic factors or mediators of the inflammatoryresponse. Moreover, glial cells are able to synthesize neurosteroids that can interact withGABAA receptors. In a previous study [2], we have reported an increased expression of therate-limiting enzyme cholesterol side-chain cleavage cytochrome P450 (P450scc), after SEin the hippocampal formation. P450scc converts cholesterol into pregnenolone. In addition,we found that the upregulation of P450scc was more pronounced in rats exposed to longerintervals of SE, and that these animals had a delayed onset of spontaneous recurrentseizures (SRSs). Finally, we have shown that when treated with the 5α-reductase inhibitorfinasteride, a drug that blocks the synthesis of allopregnanolone, the appearance of SRSswas anticipated. We have recently identified a highly predictable lesion in the CA3 stratumlacunosum-moleculare of pilocarpine-treated adult rats [3]. This lesion enlarged withlonger SE intervals and was partially reduced or, in some cases, prevented by treatinganimals with diazepam. In addition, the CA3 lesion was uncommon in young (3-weekold)rats. A characteristic of the CA3 lesion was its association with an increasedpropensity to develop SRSs.Here, we investigated whether the higher expression of P450scc associated with glialreactivity could influence the development of the CA3 lesion as well as the frequency ofoccurrence of SRSs in both young and adult rats. To this aim, we exposed 8 and 3-weekoldrats to 1 h of SE, characterizing both the consequent brain damage and epileptogenesis.Adult animals presented a well defined lesion in CA3, consisting of loss of glial cells (Fig.1), nerve fibers and neurons. Brains in young rats, instead, presented a pronounced, longlastingglial reaction in the same area in which the CA3 lesion was localized in adultanimals. As expected, young rats presented with P450scc induction that was larger than inadults. In addition, spontaneous seizures were significantly delayed (p<0.01) in younganimals exposed to 1 h SE compared with adults. To further evaluate the role ofneurosteroids on the onset of the CA3 lesion we treated the adult group (which presentsthis type of damage) with ganaxolone (60 mg/kg p.o.), a synthetic analogue ofallopregnanolone. Ganaxolone was able to significantly prevent the CA3 lesion in 3/13,whereas all untreated rats (n=10) were damaged. However, no differences were found inthe onset of SRSs in both groups of treatment (Fig. 2). Taken together, these resultssuggest that high levels of neurosteroids protect the CA3 hippocampal region from damageoccurring during SE. However, this effect was particularly evident in young rats. Theallopregnanolone analogue ganaxolone only modestly prevented the lesion in adult rats;such a lesion is known to be prevented by diazepam administration (3). These findingssuggest that endogenous neurosteroids are more effective than those administered exogenously. We propose that the development of more effective neurosteroid mimeticdrugs could provide promising tools for the treatment of temporal lobeepilepsy.

Neuroprotective effects of neurosteroids in pilocarpine-treated rats / Longo, Daniela; Silvestri, Chiara; M. A., Rogawski; M., Avoli; Biagini, Giuseppe. - In: TRABAJOS DEL INSTITUTO CAJAL. - ISSN 0211-8343. - STAMPA. - LXXXII:(2009), pp. 121-122. ((Intervento presentato al convegno 5th International Meeting STEROIDS AND NERVOUS SYSTEM tenutosi a Torino nel 13-18 febbraio 2009.

Neuroprotective effects of neurosteroids in pilocarpine-treated rats

LONGO, Daniela;SILVESTRI, Chiara;BIAGINI, Giuseppe
2009-01-01

Abstract

The pilocarpine model is based on status epilepticus (SE) induction in rodents to mimictemporal lobe epilepsy as observed in humans. Depending on SE duration, widespreaddamage is observed in hippocampal or extrahippocampal regions leading to gliosis andreorganization of neuronal circuits [1]. Glial cells can play a role in modulating the lesionoutcome through the release of neurotrophic factors or mediators of the inflammatoryresponse. Moreover, glial cells are able to synthesize neurosteroids that can interact withGABAA receptors. In a previous study [2], we have reported an increased expression of therate-limiting enzyme cholesterol side-chain cleavage cytochrome P450 (P450scc), after SEin the hippocampal formation. P450scc converts cholesterol into pregnenolone. In addition,we found that the upregulation of P450scc was more pronounced in rats exposed to longerintervals of SE, and that these animals had a delayed onset of spontaneous recurrentseizures (SRSs). Finally, we have shown that when treated with the 5α-reductase inhibitorfinasteride, a drug that blocks the synthesis of allopregnanolone, the appearance of SRSswas anticipated. We have recently identified a highly predictable lesion in the CA3 stratumlacunosum-moleculare of pilocarpine-treated adult rats [3]. This lesion enlarged withlonger SE intervals and was partially reduced or, in some cases, prevented by treatinganimals with diazepam. In addition, the CA3 lesion was uncommon in young (3-weekold)rats. A characteristic of the CA3 lesion was its association with an increasedpropensity to develop SRSs.Here, we investigated whether the higher expression of P450scc associated with glialreactivity could influence the development of the CA3 lesion as well as the frequency ofoccurrence of SRSs in both young and adult rats. To this aim, we exposed 8 and 3-weekoldrats to 1 h of SE, characterizing both the consequent brain damage and epileptogenesis.Adult animals presented a well defined lesion in CA3, consisting of loss of glial cells (Fig.1), nerve fibers and neurons. Brains in young rats, instead, presented a pronounced, longlastingglial reaction in the same area in which the CA3 lesion was localized in adultanimals. As expected, young rats presented with P450scc induction that was larger than inadults. In addition, spontaneous seizures were significantly delayed (p<0.01) in younganimals exposed to 1 h SE compared with adults. To further evaluate the role ofneurosteroids on the onset of the CA3 lesion we treated the adult group (which presentsthis type of damage) with ganaxolone (60 mg/kg p.o.), a synthetic analogue ofallopregnanolone. Ganaxolone was able to significantly prevent the CA3 lesion in 3/13,whereas all untreated rats (n=10) were damaged. However, no differences were found inthe onset of SRSs in both groups of treatment (Fig. 2). Taken together, these resultssuggest that high levels of neurosteroids protect the CA3 hippocampal region from damageoccurring during SE. However, this effect was particularly evident in young rats. Theallopregnanolone analogue ganaxolone only modestly prevented the lesion in adult rats;such a lesion is known to be prevented by diazepam administration (3). These findingssuggest that endogenous neurosteroids are more effective than those administered exogenously. We propose that the development of more effective neurosteroid mimeticdrugs could provide promising tools for the treatment of temporal lobeepilepsy.
LXXXII
121
122
Longo, Daniela; Silvestri, Chiara; M. A., Rogawski; M., Avoli; Biagini, Giuseppe
Neuroprotective effects of neurosteroids in pilocarpine-treated rats / Longo, Daniela; Silvestri, Chiara; M. A., Rogawski; M., Avoli; Biagini, Giuseppe. - In: TRABAJOS DEL INSTITUTO CAJAL. - ISSN 0211-8343. - STAMPA. - LXXXII:(2009), pp. 121-122. ((Intervento presentato al convegno 5th International Meeting STEROIDS AND NERVOUS SYSTEM tenutosi a Torino nel 13-18 febbraio 2009.
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