Is Mossy Fiber Sprouting a Potential Therapeutic Target for Epilepsy?

Mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis is one of the most frequent focal epilepsies in adults. It is characterized by focal seizures that begin in the hippocampus, sometimes spread to the insulo-perisylvian regions and may progress to secondary generalized seizures. Morphological alterations in hippocampal sclerosis are well defined. Among them, hippocampal sclerosis is characterized by prominent cell loss in the hilus and CA1, and abnormal mossy fiber sprouting (granular cell axons) into the dentate gyrus inner molecular layer. In this review, we highlight the role of mossy fiber sprouting in seizure generation and hippocampal excitability and discuss the response of alternative treatment strategies in terms of MFS and spontaneous recurrent seizures in models of TLE (temporal lobe epilepsy)

Maximal electroshock-induced seizures are able to induce Homer1a mRNA expression but not pentylenetetrazole-induced seizures

Objective: Homer1a is a protein that regulates metabotropic glutamate receptors involved in neural plasticity processes. Recently, we demonstrated that Homer1a mRNA is enhanced after pilocarpine-induced status epilepticus. Here, we investigated whether a single acute seizure triggered by means of pentylenetetrazole (PTZ) injection or maximal electroshock (MES) stimulation (2 different seizure models) would alter Homer1a expression in the hippocampus.Methods: Male Wistar rats subjected to the PTZ or MES model were analyzed 2 h, 8 h, 24 h, and 7 days after seizure induction. Homer1a, mGluR1, and mGluR5 mRNA expression levels in hippocampal extracts were analyzed by quantitative PCR.Results: Quantitative PCR revealed Homer1a overexpression at 2 h after MES-induced tonic-clonic seizures compared to control, but the overexpression did not remain elevated after 8 h. Pentylenetetrazole-induced seizures, in contrast, were not able to change Homer1a mRNA expression. No differences were observed at these time points after seizures for mGluR1 and mGluR5 mRNA expression in any of the models.Significance: Our data indicate that the levels of Homer1a mRNA were transiently increased only after MES induced tonic-clonic seizures (and not after PTZ-induced seizures). We suggest that Homer1a expression may be dependent on seizure intensity or on specific brain circuit activation. We suggest that Homer1a may contribute to counteract hyperexcitability processes. (C) 2015 Elsevier Inc. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Physiol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, UNONEX, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, UNONEX, BR-04023062 São Paulo, BrazilFAPESP: 05/57278-4Web of Scienc

Reduced hippocampal dentate cell proliferation and impaired spatial memory performance in aged epileptic rats

Increased adult neurogenesis is observed after training in hippocampal-dependent tasks and also after acutely induced status epilepticus (SE) although the specific roles of these cells are still a matter of debate. In this study, we investigated hippocampal cell proliferation and differentiation and the spatial learning performance in young or aged chronically epileptic rats. Status was induced by pilocarpine in 3 or 20-month old rats. Either two or twenty months later, rats were treated with bromodeoxyuridine (BrdU) and subsequently underwent to 8-day schedule of water maze tests. As expected, learning curves were faster in young than in aged animals (P<0.001). Chronically epileptic animals exhibited impaired learning curves compared to age-matched controls. Interestingly, the duration of epilepsy (2 or 20 months) did not correlate with the memory impairment of aged epileptic animals. The number of BrdU-positive cells was greater in young epileptic subjects than in age-matched controls. In contrast, cell proliferation was not increased in aged epileptic animals, irrespective of the time of SE induction. Finally, dentate cell proliferation was not related to performance in the water maze. Based on the present results we conclude that even though aging and epilepsy lead to impairments in spatial learning, their effects are not additive

Effective Topical Treatment of Subcutaneous Murine B16F10-Nex2 Melanoma By the Antimicrobial Peptide Gomesin1

Gomesin is a potent antimicrobial peptide (AMP) isolated from hemocytes of the spider Acanthoscurria gomesiana. The present study aimed at determining whether gomesin exerted antitumor activity in vitro and in vivo. Topical treatment of subcutaneous murine melanoma with gomesin incorporated in a cream base significantly delayed tumor growth. A direct cytotoxicity of gomesin in murine melanoma B16F10-Nex2 cells and several human tumor cell lineages was observed in vitro, with IC50 values below 5 µM. The β-hairpin structure of gomesin with disulfide bridges seemed essential for optimal activity. d-Gomesin was equally active. A membrane-permeabilizing activity was suggested, as gomesin bound to the cell membrane and cytoplasmic lactate dehydrogenase was detected extracellularly. At doses causing partial growth of tumor cells, gomesin allowed internalization of macromolecules (immunoglobulins), which increased the cytotoxic effect. The in vivo antitumor effect of gomesin might also involve a cytotoxic effect on endothelial cells because cultured human endothelial cells were killed in vitro at a similar concentration range. This effect represents a novel and potential use for gomesin as a topical agent against unsuccessfully treated intradermal and epithelial skin cancers. To our knowledge, this is the first report on the successful topical use of AMPs in cancer treatment