Adenosine A(2A) receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

During brain ischemia, excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage. Indeed, anoxic depolarization, consisting of massive neuronal depolarization due to the loss of membrane ion gradients, occurs in vivo or in vitro during an energy failure. The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors, namely: A(1), A(2A), A(2B), and A(3). The A(2A) receptor subtype is highly expressed in striatal medium spiny neurons, which are particularly susceptible to ischemic damage. Evidence indicates that the A(2A) receptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours. We recently added new knowledge to the mechanisms by which the adenosine A(2A) receptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation. We demonstrated that the selective block of A(2A) receptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K(+) channel modulation and a presynaptic inhibition of glutamate release by the A(2A) receptor antagonist. The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A(2A) receptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.