Differential Expression of Cerebellar Metabotropic Glutamate Receptors mGLUR2/3 and mGLUR4a after the Administration of a Convulsant Drug and the Adenosine Analogue Cyclopentyladenosine

Abstract

Metabotropic glutamate receptors (mGluR) play a role in synaptic transmission, neuronal modulation and plasticity but their action in epileptic activity is still controversial. On the other hand adenosine acts as a neuromodulator with endogenous anticonvulsive properties. Since cerebellum from epileptic patients has shown neuronal damage, sometimes associated with Purkinje cells loss, we have explored the effect of repetitive seizures on two types of mGluR in the cerebellum. Seizures were induced by the convulsant drug 3-mercaptopropionic acid (MP) and the effect of the adenosine analogue cyclopentyladenosine (CPA) alone or before MP administration (CPA+MP) were also evaluated. The expression of the receptors subtypes 2/3 (mGluR2/3) and 4a (mGluR4a) was assessed by immunocitochemistry. Granular cell layer was labeled with mGluR2/3 antibody and increased immunoreactivity was observed after MP (60%), CPA (53%) and CPA + MP (85%) treatments. Control cerebellum slices showed mGluR4a reactivity around Purkinje cells, while MP, CPA and CPA+MP treatment decreased this immunostaining. Repetitive administration of MP and CPA induces an increased cerebellar mGluR2/3 and a decreased mGluR4a immunostaining, suggesting a distinct participation of both receptors that may be related to the type of cell involved. A protective action and /or an apoptotic effect may not be discarded. CPA repetitive administration although increase seizure latency, cannot prevent seizure activity.

The Changes in mGluR2 and mGluR7 Expression in Rat Medial Vestibular Nucleus and Flocculus Following Unilateral Labyrinthectomy

“…The present results demonstrated that mGluR2 expression at both the mRNA and protein levels increased in the ipsilateral flocculus at the 1st day after UL compared to both sham controls and the contralateral flocculus. Our immunohistochemical results agree with other studies [41,42] that described in the flocculus, mGluR2 present in the granule cell layer and Purkinje layer. They demonstrated that mGluR2 present in the cell body of the granular layer (dendrites and axon terminals of Golgi cells).…”

The Antiepileptic Potential of Nucleosides

“…Pentylenetetrazole-induced (intraperitoneal injection) seizures in rats and in mice Seizure reduction, anticonvulsant effect [254,256] Pentylenetetrazole-induced seizures in rats Suppressed/abolished tonic phase of generalized tonicclonic seizures [255] Bicuculline-induced (intraperitoneal injection) seizures in mice Anticonvulsant effect [254] Audiogenic seizures (audiogenic-seizure-sensitive DBA/2 mice) Seizure prevention [95] PPS (perforant path stimulation) rat model of status epilepticus Decreased progression from self-terminating seizures to selfsustaining status epilepticus (SSSE) and decreased severity of SSSE [68] Kainic acid-induced (intraperitoneal injection) seizures in rats Delayed status epilepticus presentation [235] 4-aminopyridine-induced (rat hippocampal slices) epileptiform activity Decreased epileptiform bursting duration [269] 3-mercaptopropionic acid-induced seizures Increased seizure latency [271] Aminophylline-induced (intraperitoneal application) seizures in mice Delayed time to onset of clonic convulsions [279] Bicuculline-induced (rat prepiriform cortex) seizures Seizure protection [267] Electrical stimulation rat models of status epilepticus Seizure suppression [257] CPA (A1 receptor agonist)…”

“…3A) [118,168,216,237] and D-, L-, R-and S-N 6 -(2-phenylisopropyl) adenosine (D-, L-, R-and S-PIA; A 1 agonists) ( Table 3; Fig. 3A) [118,168,180] were effective against bicuculline-and/or kainicacid-, pilocarpin-, 3-nitropropionic-acid-, 3-mercaptopropionicacid-and PTZ-induced seizures/epileptiform activity as well as 4-aminopyridine-induced epileptiform bursting activity [235,[265][266][267][268][269][270][271] and in the rat kindling model [119,[272][273][274][275][276][277]. It has also been demonstrated that R-PIA prolonged the latency to convulsions in a hypoxia-induced model [278] and CPA delayed the time onset of clonic convulsions in aminophylline-induced seizures [279].…”

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

“…This technique was applied as previously described (Girardi et al 2007). In brief, 24 h after last injection, animals were deeply anaesthetized with 300 mg/kg of chloral hydrate, perfused and fixated.…”

“…The repetitive administration of the convulsant drug 3-mercaptopropionic acid (MP) induces tonic-clonic seizures and reactive astrogliosis in CNS (Girardi et al 2004), and the administration of the adenosine analogue cyclopentyladenosine (CPA) increases seizure threshold (Girardi et al 2007). Adenosine-a neuromodulator with endogenous anticonvulsant properties-inhibits neuronal firing and synaptic transmission acting mainly via A1 receptors, the most abundant of the four kinds of adenosine receptors described (Dunwiddie andMasino 2001, Ribeiro et al 2003), being cerebellum, a rich region in A1 receptors (Giraldez et al 1998).…”