title: Exogenous protein Hsp70/Hsc70 can penetrate into brain structures and attenuate the severity of chemically-induced seizures.
abstract: Heat shock protein 70 kDa (Hsp70) possesses a remarkable neuroprotective activity and the results of recent studies demonstrated its efficacy in the attenuation of epileptic seizures. The aim of this study was to explore the effects of a pure Hsp70/Hsc70 preparation delivered to the brain regions involved in generalized seizures induced in rats by intracerebroventricular microinjections of NMDA or systemic injections of pentylenetetrazole. Purified Hsp70/Hsc70 was administered (intracerebroventricular) 2 h before the induction of seizures. Compared to the vehicle-treated control animals, Hsp70/Hsc70-pretreated rats demonstrated reduced severity of NMDA- and pentylenetetrazole-induced seizures. To identify the brain structures potentially implicated in the Hsp70/Hsc70-mediated anticonvulsant effect, we analysed the localization of a fluorescently-labelled chaperone in the brain. Labelled Hsp70/Hsc70 was found in neurons and terminals of the limbic seizure complex of the brain and was co-localized in these regions with NMDA receptors, synaptophysin and the GABA-synthesizing enzyme, L-glutamic acid decarboxylase 67. An immunoprecipitation assay confirmed interactions between Hsp70 and both synaptophysin and L-glutamic acid decarboxylase 67 in brain tissue. We suggest that the anticonvulsant effect of exogenous Hsp70/Hsc70 is not only based on its protective capacity but is also related to its ability to modulate GABA neurotransmission, which in turn contributes to the maintenance of the excitatory-inhibitory balance of the CNS.
authors.affiliation: Laboratory of Comparative Thermophysiology, IM Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Ekimova
authors.forename: Larisa E
authors.initials: LE
authors.lastname: Nitsinskaya
authors.forename: Irina V
authors.initials: IV
authors.lastname: Romanova
authors.forename: Yuri F
authors.initials: YF
authors.lastname: Pastukhov
authors.forename: Boris A
authors.initials: BA
authors.lastname: Margulis
authors.forename: Irina V
authors.initials: IV
authors.lastname: Guzhova
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002417:Cattle; D050883:HSC70 Heat-Shock Proteins / Q000502:physiology* / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D010433:Pentylenetetrazole / Q000633:toxicity; D011446:Prospective Studies; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D012720:Severity of Illness Index
chemical_list: D000927:Anticonvulsants; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D011994:Recombinant Proteins; D016202:N-Methylaspartate; D010433:Pentylenetetrazole