Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2). (9th February 2016)

• Record Type: Journal Article
• Authors: Mohamed, R.A.; Agha, A.M.; Abdel-Rahman, A.A.; Nassar, N.N.
• Is Part Of: Neuroscience. Volume 314(2016)
• Page Start: 145
• Page End: 159
• Publication Date: 2016-02-09
• Subjects: BDNF brain-derived neurotropic factor -- cAMP cyclic adenosine monophosphate -- CGS21680 3-[4-[2-[[6-amino-9-[(2R, 3R, 4S, 5S)-5-(ethylcarbamoyl)-3, 4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid – selective adenosine A2A agonist -- Cyt. c cytochrome c -- DAG diacyl glycerol -- ELT escape latency time -- Glu glutamate -- IL-10 interleukin-10 -- iNOS inducible nitric oxide synthase -- IR ischemia reperfusion -- MWM morris water maze -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- Nrf-2 nuclear factor (erythroid-derived 2)-like 2 -- OFT open field test -- PBS phosphate-buffered saline -- pCREB phosphorylated cAMP response element-binding protein -- PD98059 mitogen-activated protein kinase (MAPK) extracellular signaling-regulated kinase kinase inhibitor -- pERK1/2 phospho-extracellular signal-regulated kinases 1 and 2 -- PKA protein kinase A -- PKC protein kinase C -- SCH58261 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4, 3-e]-1, 2, 4-triazolo[1, 5-c]pyrimidine – selective adenosine A2A antagonist -- SO sham operated -- TBARS thiobarbituric acid reactive substances -- TNF-α tumor necrosis factor-alpha -- TTC triphenyltetrazolium chloride; A2A -- ischemia reperfusion -- pERK1/2 -- microglia -- apoptosis -- oxidative stress; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.11.059
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: A2A R activates pERK1/2 in a DAG-dependent pathway in a cerebral IR model. SCH58261 protects against cerebral IR by inhibiting pERK1/2 in hippocampal neurons. SCH58261 and PD98059 decrease excitotoxicity, inflammatory and apoptotic mediators. Abstract: Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2A R to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. Male Wistar rats (250–270 g) subjected to bilateral carotid occlusion for 45 min followed by a 24-h reperfusion period showed increased infarct size corroborating histopathological damage, memory impairment and motor incoordination as well as increased locomotor activity. Those events were mitigated by the unilateral intrahippocampal administration of the selective A2A antagonist SCH58261 via a decrease in pERK1/2 downstream from diacyl glycerol (DAG) signaling. Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-α) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance.