Abstract
Adenosine is a ubiquitous signaling molecule, with widespread activity across all organ systems. There is evidence that adenosine regulation is a significant factor in traumatic brain injury (TBI) onset, recovery, and outcome, and a growing body of experimental work examining the therapeutic potential of adenosine neuromodulation in the treatment of TBI. In the central nervous system (CNS), adenosine (dys)regulation has been demonstrated following TBI, and correlated to several TBI pathologies, including impaired cerebral hemodynamics, anaerobic metabolism, and inflammation. In addition to acute pathologies, adenosine function has been implicated in TBI comorbidities, such as cognitive deficits, psychiatric function, and post-traumatic epilepsy. This review presents studies in TBI as well as adenosine-related mechanisms in co-morbidities of and unfavorable outcomes resulting from TBI. While the exact role of the adenosine system following TBI remains unclear, there is increasing evidence that a thorough understanding of adenosine signaling will be critical to the development of diagnostic and therapeutic tools for the treatment of TBI.
Highlights
NEUROPHYSIOLOGY OF THE ADENOSINE SYSTEMThe A1 and A2A receptors are widely expressed in brain, with high adenosine affinity (~100nM [38]), and complementary actions
Adenosine is a ubiquitous signaling molecule, with widespread activity across all organ systems
3'-5'-cyclic adenosine monophosphate is a key component of the adenosine metabolic pathway (Fig. (2)). cAMP is a second messenger regulated by G-protein coupled receptors which serve to rapidly couple extracellular signals to intracellular responses. cAMP is is modulated by diverse extracellular signals, including hormones, dopamine, glutmate, and adenosine
Summary
The A1 and A2A receptors are widely expressed in brain, with high adenosine affinity (~100nM [38]), and complementary actions. Adenosine appears to act as the unifying signaling molecule in studies of the molecular basis of learning [34] It acts as an autocrine signaling molecule at the tetanized synapse, enhancing synapse strength via A2A receptor activation [4]. It acts as a paracrin signal via a calcium wave in the astrocytic syncitium, acting distant from the tetanized synapse to achieve heterosynaptic depression by A1 receptor activation [58] In addition to their role at the synapse, astrocytes release Ado at endothelial cells, causing vasodilation via A2A receptor activation, which enhances local circulation and provides the additional metabolic support rquired during intense synaptic stimulation [61]. A more complicated response has been revealed, with A3 receptor activation protecting CA1 neurons during short duration oxygen-glucose deprivation, yet causing damage during long-duration depriviation [116]
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