3-Mercaptopropionic Acid-Induced Repetitive Seizures Increase GluN2A Expression in Rat Hippocampus: A Potential Neuroprotective Role of Cyclopentyladenosine

Abstract

The N-methyl-D-aspartate receptor (NMDAR) is involved in synaptic plasticity, learning, memory, and neurological diseases like epilepsy and it is the major mediator of excitotoxicity. Functional NMDARs in the mature brain are heteromeric complexes composed of different subunits: GluN1 and GluN2. There are four different GluN2 subunits (A-D) and each of them critically determines the pharmacological and electrophysiological properties of NMDARs. GluN1 is ubiquitously expressed in the central nervous system while the highest GluN2A expression is in the hippocampus. Adenosine, an endogenous anticonvulsant, is a neuromodulator with a critical role in the regulation of neuronal activity, mediating its effect on specific receptors, among which adenosine A1 receptor is highly expressed in the hippocampus. In the present work hippocampal GluN2A expression after the convulsant drug 3-mercaptopropionic acid (MP) induced seizures and the effect of cyclopentyladenosine (CPA) given alone or prior to MP (CPA + MP) in an acute or repetitive experimental model was studied. CPA administered to rats for one or 4 days increases seizure threshold induced by MP. After one administration of MP, no significant difference in GluN2A expression was observed in CPA and CPA + MP by Western blot, although immunohistochemistry revealed an increase in CA2/3 area. However, repetitive MP administration during 4 days showed a significant increase of GluN2A expression, and the repetitive administration of CPA 30 min prior to MP caused a significant decrease of GluN2A expression with respect to MP treatment, returning to control levels. These results show that GluN2A subunit is involved in repetitive MP-induced seizures, while CPA administration displays a protective effect against it.

Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats

“…Contradictory data about NMDAR subunit expression were obtained in other experimental models. A significant reduction in the production of the GluN2B subunit in various regions of the hippocampus and cerebellum and an increase in the expression of the GluN2A subunit are revealed after repetitive seizures, induced by repeated administration (4–7 days) of convulsant drug 3-mercaptopropionic acid (Auzmendi et al, 2009 ; Girardi et al, 2010 ; Gori and Girardi, 2013 ). A significant increase of GluN2A, but not of GluN2B expression in the immunohistochemical analysis was obtained after repeated epileptic seizures induced for 12 days by intraperitoneal administration of 4-aminopyridine (Borbely et al, 2009 ).…”

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

“…Injection of convulsive agents, such as 3-mercaptopropionic acid or 4-aminopyridine for several days, is able to increase hippocampal GluN2A levels [181,182]. Chen and colleagues demonstrated how selective antagonism of the GluN2 subunits is neuroprotective in the hippocampus of pilocarpine and kindling animal models of epilepsy.…”

New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice

“…This technique was applied as previously described (Gori and Girardi, 2013) with certain modifications.…”