A1 is the most abundant AR subtype in the brain with broad distribution in neurons of the cortex, hippocampus, and cerebellum.31,58 Several studies have shown that activation of adenosine A1R promoted neuroprotection, induced sedation, reduced anxiety, inhibited seizures,76 and reduced A1R exacerbated neuronal damage.58 Significant reduction in A1R expression was detected in layers of the dentate gyrus in the brain of AD subjects,68,77 providing evidence that A1R agonists might be an effective therapy for treatment of AD even at late stages of the disease.78 Additionally, A1R agonists or adenosine reuptake inhibitors have shown to decrease the extent of brain damage in most brain injuries.78,79 There are evidences of increased microglial proliferation; enhanced matrix metalloproteinase 12 (MMP-12) expression, inducible nitric oxide synthase, and pro-inflammatory interleukin-1β (IL-1β); and exacerbated demyelination in MS and neuronal injury in A1R knockdown animal models.80,81 The positive effect of A1Rs activation in the CNS suggests that this receptor could be one of the most promising targets for the development of novel drugs with neuroprotective effect for the treatment of neurological and psychiatric disorders.69
