Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC) antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i). These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.
Highlights
A recent meta-analysis examining the prevalence of Traumatic brain injury (TBI) in the general adult population found that that approximately 12% of the general adult population has a history of TBI with loss of consciousness
In this paper we review the role of voltage gated calcium channels (VGCC) in the pathophysiology of TBI, and evidence that antagonists of VGCC can be neuroprotective in animal models of TBI and may have potential for clinical use
Astrocytes have L- and possibly T-type channels, while, to date, VGCCs have not been observed on mature oligodendrocytes [77]
Summary
It is estimated that well over 5.3 million people live in the United States with deficits related to traumatic brain injury (TBI) [1], with over 1.7 new TBI cases annually. In a recent study by the TBI Model Systems National Data Centre only 38% of patients followed were employed 2-years following their TBI [8]. $48.3 billion dollars is spent on TBI patient care in the US each year, with over $31.7 billion (65%) for those that survive [9]. The annual cost for new cases of acute TBI care and rehabilitation is estimated to be approximately $10 billion in the U.S alone. The need to develop effective drugs for TBI continues to be pressing. In this paper we review the role of voltage gated calcium channels (VGCC) in the pathophysiology of TBI, and evidence that antagonists of VGCC can be neuroprotective in animal models of TBI and may have potential for clinical use
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