Adenosine impacts cerebral ischemia reperfusion (IR) through the inhibitory A and the excitatory A receptors. The present study aimed at investigating the contrasting role of pERK1/2 in mediating adenosine AR (protective) versus AR (deleterious) effects in IR. Male Wistar rats subjected to bilateral carotid occlusion (45 min) followed by reperfusion (24 h) exhibited increased pERK1/2 activity, downstream from DAG pathway, along with increases in hippocampal glutamate, c-Fos, NF-κB, TNF-α, iNOS, TBARS, cytochrome c, caspase-3, BDNF, Nrf2, and IL-10 contents. Further, hippocampal microglial reactivity, glial TNF-α, and BDNF expression were observed. Although unilateral intrahippocampal injection of either the AR agonist CHA or the AR agonist CGS21680 increased pERK1/2, only CHA mitigated histopathological and behavioral deficits along with reducing glutamate, microglial activation, c-Fos, TNF-α, iNOS, TBARS, cytochrome c and caspase-3 and elevating Nrf2 and IL-10 levels in IR rats. These results yield insight into the double-faceted nature of pERK1/2 in mediating protective and deleterious effects of AR and AR signaling, respectively, against IR injury.

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The use of Monosodium Glutamate (MSG) as a food flavor enhancer is increasing worldwide despite its neurotoxic effects. Fluoxetine (FLX) and Rosemary extract (RE) are known to have beneficial neuroprotective properties. Rats were divided into five groups: control group; MSG group, rats received 2 g/kg/day intraperitoneal (i.p.) injections of MSG for seven days; RE/MSG group, rats received 50 mg/kg/day of oral RE for 28 days starting prior to MSG; FLX/MSG group, rats received 10 mg/kg/day of oral FLX for 28 days beginning before MSG; and RE/FLX/MSG group, received combined treatments as mentioned above. Rats underwent the Barnes maze test, in addition to histopathological, immunohistochemical, morphometric and ultrastructural evaluations for their hippocampi. MSG increased the number of errors and escaped latency in the Barnes maze test that was significantly minimized in the three treatment groups. The MSG group exhibited pyramidal cell (PC) degeneration, shrunken glial cells and massive vascular dilatation that were improved with RE and/or FLX treatment. The number of glial fibrillary acidic protein (GFAP)-immunopositive cells were increased, and the number of PCs was decreased in the MSG group, while these values were significantly reversed with the three treatment groups with the most significant improvement at RE/FLX/MSG one. Ultrastructurally, PCs were shrunken with degenerated nuclei, dilated endoplasmic reticulum, swollen mitochondria, and vacuolations in the MSG group that were improved with RE and/or FLX. In conclusion, the combined RE and FLX treatment can ameliorate the toxic effect of MSG on rat hippocampus probably through its antioxidant and anti-inflammatory effects.

Global cerebral ischemia reperfusion (IR) following cardiac arrest, shock and asphyxia can affect wide brain areas where new therapies are imperative. Moreover, many intracellular pathways mediating tissue response to IR are still elusive. Adenosine is a neuromodulator that greatly impacts IR through the inhibitory A1 and excitatory A2 receptors. Studies indicate that both adenosine A1 agonists and A2A antagonists are neuroprotective during ischemic insults. However, many of the signaling pathways affecting such responses are largely unknown. In the current study, bilateral carotid occlusion for 45 min. followed by 24h reperfusion period resulted in histopathological damage as well as memory impairment, motor incoordination and increased locomotor activity. Such events were attenuated by unilateral intra‐hippocampal injection of both the selective A1 agonist N6‐cyclohexyl adenosine (CHA) and the A2A antagonist 7‐(2‐phenylethyl)‐5‐amino‐2‐(2‐furyl)‐pyrazolo‐[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine (SCH58261). On the cellular level, IR increased glutamate, pERK1/2, c‐Fos, NF‐kB, TNF‐α, cytochrome c, caspase‐3, BDNF, Nrf2 and IL‐10 contents. Both CHA and SCH58261signifiantly reduced glutamate, c‐Fos, TNF‐α, cytochrome c, caspase‐3 and increased Nrf‐2 and IL‐10 contents. While only SCH58261 reduced pERK1/2, NF‐kB and BDNF contents. By the same token, iNOS and TBARS levels were increased following IR and attenuated by both CHA and SCH58261 treatments. Accordingly, these results lend insight to the neuroprotective effects of A1 and A2A agonists and antagonists respectively where pERK1/2 and NF‐kB pathways might be involved in adenosine mediated attenuation of inflammation, apoptosis and oxidative stress.

Adenosine is a potent biological mediator, the concentration of which increases dramatically following brain ischemia. Out of the four known adenosine receptor subtypes (A1, A2A, A2B and A3), the A2A is of critical importance in stroke. Although, both A2A agonists and antagonists are proven protective during ischemia reperfusion (IR) injury, however, ,the mechanisms by which A2A receptors are noxious during IR remain elusive. The objective of the present study was to investigate the role of central A2A receptor in modulating cellular as well as behavioral responses to IR injury and the possible involvement of ERK signalling pathway. Hence, we hereby report that bilateral carotid occlusion for 45 min followed by 24h reperfusion period resulted in a significant memory impairment, motor incoordination as well as increased locomotor activity that were not affected by unilateral intrahippocampal injection of a selective A2A agonist CGS21680, but conversely mitigated by the selective A2A antagonist SCH58261. On the cellular level, IR increased the pERK, NFkB, cytochrome c, BDNF, Nrf2 and TNF‐α content in the hippocampus. With the exception of Nrf2 level, treatment with SCH58261 significantly reversed these effects, however, CGS21680 treatment resulted in a non‐significant change from IR insult. Accordingly these results suggest a possible protective role of the central A2A receptor blockade in IR injury with a prospective involvement of p42/44 pathway.