Purinergic signaling in Stroke and Multiple Sclerosis: Prospects for therapies

Stroke and multiple sclerosis involve oxygen and nutrient deprivation in the brain as well as inflammation, all of which lead to the release of glutamate and ATP. These compounds can cause excitotoxicity, contributing to neuronal and glial damage. Purinergic signaling, mediated by ATP and adenosine, regulates neuroinflammatory and neuroprotective mechanisms, playing a pivotal role in CNS injury. Key elements such as pannexin-1 hemichannels, calcium homeostasis modulator-1 (CalHM1), purinergic P2X7 receptors, and downstream intermediaries of ATP release contribute to neurotoxicity and inflammatory processes. Notably, P2X7 and P2X4 receptors are critical targets for reducing neuronal damage caused by microglia-mediated inflammation and repair, respectively. Additionally, the interaction between purinergic signaling and GABA type A (GABA_A) receptors opens new therapeutic possibilities by potentially promoting a balance in neurotransmission modulation and mitigating excitotoxicity. Experimental evidence and recent pharmacological developments, including P2X7 antagonists, P2X4 positive allosteric modulators, P1 agonists, and modulators of GABA_A receptors, offer promising avenues for translating preclinical findings into effective therapies for cerebrovascular diseases. Further clinical investigations are necessary to validate these interventions to attenuate tissue damage and foster repair in multiple sclerosis lesions and post-ischemic penumbra.