Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs

Chronic agomelatine treatment suppresses the kainate-induced glial reaction during epileptogenesis in rats

Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. The aim of this study was to examine the effect of the novel antidepressant agomelatine (Ago), a po­tent melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist, on glial activity during kainate (KA)-induced epileptogenesis.Brain sections were immunostained with the microglial marker Iba-1 and two astrocyte-specific markers, GFAP and S100 beta, and the glial cell morphology in brain structures vulnerable to KA-induced neurotoxicity was de­scribed in the KA-treated groups and their matched controls, respectively.Both control and Ago-treated groups were characterized with ramified microglial cells with fine processes. After administration of KA, activated Iba-1-immunoreactive microglial cells in the dorsal and ventral hippocampus, dentate gyrus, as well as in the basolateral amygdala (BLA) and piriform cortex were increased in number and displayed enlarged round-shaped bodies and arborization. Chronic Ago treatment during epileptogenesis sig­nificantly diminished their number compared to that in the matched vehicle-treated epileptic group, specifical­ly in the CA1a, CA1b, CA1c and CA3c subfields of dorsal hippocampus, BLA and piriform cortex. Conversely, the KA-induced reactive astrogliosis was more restricted and both GFAP- and S100 beta-immunostained cells were observed mainly in the CA1 and CA3c fields of dorsal hippocampus and piriform cortex. The Ago treatment did not significantly reduce the number of immunopositive astrocytes in the CA2, CA3a, CA3b subfields of the dor­ sal and CA1, CA2, CA3 subfields of the ventral hippocampus, the dentate gyrus and the BLA. In addition, only a few immunostained ramified astrocytes were scattered in the ventral hippocampus of the KA-veh group, while the Ago-treated group showed a considerable increase of immunoreactive cells in this area compared to controls.The present results show that chronic Ago treatment during epileptogenesis prevents the KA-induced microglial activation and suppresses the neuronal cell death in the vulnerable limbic regions. It can provide effective ther­apy for brain disorders involving neuronal damage, neuroinflammation and oxidative stress such as epilepsy

Data for: Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice

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Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling.

Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. In the present study, we tested the hypothesis that the novel antidepressant agomelatine, a potent melatonin MT1, and MT2 receptor agonist and serotonin 5FIT(2c) receptor antagonist, can prevent depressive symptoms developed during the chronic epileptic phase by suppressing an inflammatory response. Chronic treatment with agomelatine (40 mg/kg, i.p.) was initiated an hour after the kainate acid (KA)-induced status epilepticus (SE) and maintained for a period of 10 weeks in Wistar rats, Registration of spontaneous motor seizures was performed through a video (24 h/day) and EEG monitoring. Antidepressant activity of agomelatine was explored in the splash test, sucrose preference test (SPT) and forced swimming test (FST) while anxiolytic effect was observed through the novelty suppression-feeding test (NSFT) during chronic phase in epileptic rats. The frequency of motor seizures detected by video and EEG recording did not differ between vehicle and Ago group. Rats with registered spontaneous motor seizures showed symptoms typical for depressive behavior that included decreased grooming, anhedonia during the dark period and hopeless-like behavior. Epileptic rats exhibited also anxiety with novelty-induced hypophagia. This behavioral deficit correlated with increased signal markers of inflammation (plasma levels of interleukin (IL)-1 beta and activated glia in brain), while plasma corticosterone levels were not changed. Agomelatine treatment during epileptogenesis exerted a clear antidepressant effect by suppressing all behavioral hallmarks, reducing plasma IL-1 beta levels and preventing microgliosis and astrogliosis in specific limbic regions. The present results suggest that agomelatine treatment starting after SE can provide an effective therapy of comorbid depression in chronic epileptic condition through suppression of inflammatory signaling

Kainate-induced changes and the effect of losartan on angiotensin AT1 receptor expression in limbic structures in a rat model of comorbid hypertension and epilepsy

It is known that epilepsy causes elevation of components of the renin-angiotensin system in the hippocampal complex. In this study, we examined the effect of losartan, a selective angiotensin II, type 1 (AT1) receptor antag­onist, on the expression of the latter in a model of kainic acid-induced temporal lobe epilepsy and comorbid hy­pertension in normotensive Wistar rats and naive spontaneously hypertensive rats (SHRs). Immunohistochem­istry revealed that in the dorsal hippocampus AT1 receptor protein expression was enhanced in SHRs compared to that in normotensive rats. However, fewer AT1 receptor-immunoreactive cells were seen in the piriform cortex and the basolateral amygdala of SHRs. After kainate-induced status epilepticus, there was an increase in neuro­nal expression of AT1 receptors in the CA1, CA2, CA3a, and CA3c fields of the hippocampus, and the hilum of the dentate gyrus while the piriform cortex of epileptic SHRs and Wistar rats displayed a decreased AT1 receptor ex­pression. In addition, an elevation in AT1 immunostaining was observed in the basolateral amygdala of epileptic SHRs but not in epileptic Wistar rats. The long-term administration of losartan exerted stronger and structure-dependent suppression of epilepsy-induced up-regulation of AT1 receptor levels in SHRs compared to Wistar rats.In conclusion, our results confirm that AT1 receptor expression is modified in epilepsy and suggest a role of this receptor subtype in comorbid hypertension and epilepsy

Losartan suppresses the kainate-induced changes of angiotensin AT(1) receptor expression in a model of comorbid hypertension and epilepsy.

Aims: Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT(1) receptor) in limbic structures, as well as the effect of the AT(1) receptor antagonist losartan in a model of comorbid hypertension and epilepsy. Main methods: The expression of AT(1) receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT(1) receptor expression in epileptic rats that were treated for a period of 4 weeks after status epilepticus. Key findings: The naive and epileptic SHRs were characterized by stronger protein expression of AT(1) receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT(1) immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT(1) receptor expression in SHRs compared to Wistar rats. Significance: Our results confirm the important role of AT(1) receptor in epilepsy and suggest that the AT(1) receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy