Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant

Abstract

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.

Keywords: Adenosine; adenosine receptors; cerebral ischemia; neuroprotection; preconditioning; stroke; treatment..

Fig. (1)

Peripheral immune involvement following ischemic brain injury. Neurons and astrocytes damaged by ischemia release pro-inflammatory factors such as TNF-α into the brain parenchyma. These pro-inflammatory molecules in turn diffuse and bind receptors on vascular endothelial cells. Activation of endothelial cells via TNF and related receptors leads to nuclear factor kappa B (NFκB) activation and nuclear translocation. In the nucleus, NFκB activity induces transcription of adhesion molecules and chemokines, including E-selectin, P-selectin, vascular cell adhesion molecule (VCAM1), intercellular adhesion molecule (ICAM1) and heparin sulfate proteoglycan. Peripheral immune cells traveling through the vasculature express receptors to adhesion molecules (i.e. PSGL-1 for selectins, α4-βintegrin for VCAM1). As they survey the body, leukocytes roll along the activated endothelium, adhere via adhesion molecules and become activated themselves, then extravasate into the brain parenchyma.

Fig. (2)

Adenosine modulates peripheral immune cell function. Adenosine modulates the activity of peripheral immune cells differentially depending on the receptors that are activated. Overall, activation of A_2A and A_2B receptors directs immune cells to an anti-inflammatory response. This property could be harnessed in stroke to reduce inflammatory damage in the CNS caused by infiltrating activated immune cells. Stimulation via A₁ receptors on immune cells tends to increase migration and activity, but also leads to angiogenesis through their interaction with cerebral vascular endothelial cells.