Developing therapeutics for traumatic brain injury remains a challenge for all stages of recovery. The pathological features of
traumatic brain injury are diverse, and it remains an obstacle to be able to target the wide range of pathologies that vary between traumatic
brain injured patients and that evolve during recovery. One promising therapeutic avenue is to target the second messengers cAMP
and cGMP with phosphodiesterase inhibitors due to their broad effects within the nervous system. Phosphodiesterase inhibitors have the
capability to target different injury mechanisms throughout the time course of recovery after brain injury. Inflammation and neuronal
death are early targets of phosphodiesterase inhibitors, and synaptic dysfunction and circuitry remodeling are late potential targets of
phosphodiesterase inhibitors. This review will discuss how signaling through cyclic nucleotides contributes to the pathology of traumatic
brain injury in the acute and chronic stages of recovery. We will review our current knowledge of the successes and challenges of using
phosphodiesterase inhibitors for the treatment of traumatic brain injury and conclude with important considerations in developing phosphodiesterase
inhibitors as therapeutics for brain trauma.
Keywords: cAMP, cognition, CREB, hippocampus, inflammation, long-term potentiation, phosphodiesterase, protein kinase A, rolipram,
synaptic plasticity, traumatic brain injury.
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