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RNAis directed toward NMDA glutamate receptors: neuromolecular basis of epilepsy and potential therapeutic approach

Grant number: 16/01703-3
Support type:Regular Research Grants
Duration: June 01, 2017 - November 30, 2019
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Renê de Oliveira Beleboni
Grantee:Renê de Oliveira Beleboni
Home Institution: Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil

Abstract

Epilepsy is a neurological disorder that affects 1-2% of the world population. Preponderant factors evolved at the onset of epilepsy are cerebrovascular diseases, brain tumors and damage, drug use, genetics, and especially uncontrolled fever in early childhood. Among the most common types of epilepsy, accounting for approximately 40-60% of cases, there is the Temporal Lobe Epilepsy (TLE). The experimental understanding of the epilepsy emergence, maintenance and progression contributes for new therapeutic approaches, with advantages in terms of efficacy and safety. Animal models that mimic with great similarity behavioral and pathophysiological conditions observed in TLE patients are of relevance. Among the most used animal models is the pilocarpine model, whose injuries in the hippocampus are of great interest. Also to this model, it is widely known the relationship between the excitatory glutamatergic receptors NMDA and the emergence, maintenance and progress of epileptic seizures, creating promising new targets for TLE treatment. Indeed, there is a marked increase in the population density and/or function of NMDA receptors in specific areas of the hippocampus and/or rearrangement of their subunits, when animals and human are affected by the status epilepticus (SE), which considerably marks the onset and maintenance of TLE. A promising new therapeutic approach and also remarkable for understanding of molecular basis of different disorders is the RNAi technique, which consists in the using from 21 to 23 nucleotides that upon degradation of complementary and corresponding mRNAs modulates the expressed product by the injection of double stranded RNA molecules (dsRNA) with potential advantages over current treatment of different disorders. Since the increased NMDA receptors expression and/or function is important for the pathophysiology of TLE, it is obvious to assume that RNAis directed to such receptors silencing may be of help, both in understanding the neuromolecular basis of epilepsy and to development of new promising therapeutic arrangements. The aim of this work will be to evaluate the selective effect of intranasal application of RNAis designed to subunits NR1, NR2A and NR2B NMDA receptors silencing, using techniques of neuroethology, electrophysiology, immunohistochemistry, neurochemistry, biochemistry, toxicology and molecular biology. Finally, this work presents a marked biotechnological interest and it promotes multidisciplinary and vanguard accomplishments when considered the new technological approaches brought by the recent biomolecular science advances. (AU)