3-Mercaptopropionic Acid-Induced Seizures Decrease NR2B Expression in Purkinje Cells: Cyclopentyladenosine Effect

Abstract

Inhibitory mechanism of cerebellum epileptic activity can be involved depending on the intensity and frequency of seizure convulsions. N-methyl-D-aspartate receptors (NMDARs) play key roles in excitatory synaptic transmission and have been implicated in neurological disorders: in cerebellum, they have specific characteristics. NMDARs are heteromeric complexes, and the expression of functional receptors in mammalian cells requires the subunit NR1 (essential) and one NR2 subtype of the four isoforms: NR2A-NR2D. In mature Purkinje cells, the combination of NR1 with NR2B subunits forms functional NMDARs; NR2B subunit may be altered in exocitotoxic events. Cyclopentyladenosine (CPA), an adenosine analogue, administered to rats, for one or more days, increases seizure threshold induced by the convulsant drug 3-mercaptopropionic acid (MP). In this study, we focused on the expression of NR2B in cerebellum after repetitive seizures induced by MP and the effect of adenosine analogue CPA administered alone or previous to MP (CPA + MP). A significant decrease in NR2B in the whole cerebellum was observed after MP and CPA administration with a tendency to recover to normal values in the combined treatment of CPA administered 30 min before MP by Western blot assay. In immunohistochemical studies, NR2B expression was observed and analysed in Purkinje cells. NR2B expression was decreased after MP (55%) and CPA (12%) administration, and CPA injected 30 min before MP led to 28% reduction in Purkinje cells. These results could be related to Purkinje cell damage or alternatively to avoid the excitotoxic effect. Results recorded after CPA + MP treatment seemed involved in decreasing the convulsant MP effect.

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 ).…”

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

“…In our work, the studied area has been the hippocampus, rich in A 1 R, and its activation by CPA inhibits the release of EAAs and hyperpolarizes the postsynaptic membrane. Girardi et al (2010) have also observed the protective effect of CPA on cerebellar GluN2B expression, an area with high expression of A 1 Rs. These results suggest that CPA would act as a protective agent to reverse the effects of MP toward control conditions acting on A 1 Rs signaling pathways (Milton et al 2008;Nayak et al 2011).…”

Adenosine Receptors and Epilepsy

“…As with neurotransmission per se , much evidence from animal research shows that this effect is A 1 R-mediated. Systemic injection of A 1 R-selective agonists limits seizures and convulsions in numerous types of experimental seizures and epilepsies (Girardi, Auzmendi, Charo, Gori, & Castro, 2010; Girardi, Canitrot, Antonelli, Gonzalez, & Coirini, 2007; Gouder, Fritschy, & Boison, 2003; Li, Kang, Shi, Liu, & Zhang, 2013; Li & Zhang, 2011; Luszczki, Kozicka, Swiader, & Czuczwar, 2005; Mares, 2010; Moezi, Akbarian, Niknahad, & Shafaroodi, 2013; Muzzi, Coppi, Pugliese, & Chiarugi, 2013; Pometlova, Kubova, & Mares, 2010; Tosh et al, 2012; Vianna, Ferreira, Doná, Cavalheiro, & da Silva Fernandes, 2005; Zuchora, Wielosz, & Urbanska, 2005). In addition, A 1 R activation augments the effects of standard AEDs (Borowicz, Łuszczki, & Czuczwar, 2002; Luszczki et al, 2005).…”