Voltage-Gated Calcium Channel Blockers for the Treatment of Traumatic Brain Injury

Traumatic Brain Injury

The most recent reports from the Centers for Disease control estimate that over 3.2 million individuals experience a traumatic brain injury (TBI) annually in the United States, with well over 5.3 million patients reporting injury-induced chronic disability ( ). A fiscal analysis indicated that the annual total cost of TBI management exceeds $221 billion dollars annually with 93% (or $205 billion dollars) associated with chronic medical care, interventions to improve quality of life, and lost wages ( ). Despite numerous clinical trials, no effective pharmacological interventions to improve outcome following TBI have been translated from the laboratory to the bedside ( ). In this chapter we review the role of calcium in posttraumatic pathophysiology, a background into voltage-gated calcium channels (VGCCs), preclinical evidence that blockers of VGCCs can reduce calcium accumulation, and subsequent glutamate release following injury and finally a description of initial clinical trials into these VGCC blockers. Our vision is that continued research into VGCC, as well as other target systems, will identify pharmacological agents that could be used to improve neurological outcome following TBI.

Traumatic Brain Injury and [Ca ²⁺ ] _i

Calcium ions (Ca ²⁺ ) are essential in the regulation of many cellular systems including release of neurotransmitters and hormones, enzyme activity, intracellular transport, contractile processes, glycolysis, respiration, mitosis, membrane potential, and intracellular communication ( ). Disruption of calcium regulation, specifically prolonged periods of elevated cytosolic free calcium, can be catastrophic for the cell leading to chronic dysfunction or death ( Fig. 11.1 ). It is therefore not surprising that TBI-induced disruption of Ca ²⁺ homeostasis contributes to cell injury and death ( ). Specifically, influx of Ca ²⁺ triggers a range of downstream effects including activation of apoptotic pathways ( ), mitochondrial dysfunction ( ), free radical production ( ), lipid peroxidation ( ), and osmotic disturbances ( ). Additional neuronal insults such as posttraumatic hypoxia ( ) and ischemia ( ) can augment the calcium-induced pathophysiology intracellular calcium ([Ca ²⁺ ] _i ) resulting in additional cell death and neuronal dysfunction. In fact, calcium has been called the “final common pathway” for toxic cell death in several pathological conditions, including TBI, stroke, and epilepsy ( ).

Injury-induced accumulation of Ca ²⁺ can trigger changes in secondary cascades within the cell such as phosphorylation of CaMKII ( ), and expression of immediate early genes, which, in turn, can lead to changes in gene transcription and translation. Subsequent changes in gene expression may be responsible for observed changes in the expression of glutamate ( ), GABA ( ), cholinergic receptors ( ), synaptic excitability ( ), as well as changes in neuronal morphology ( ). Therefore TBI-induced accumulation of [Ca ²⁺ ] _i has been linked to both cell death and dysfunction.

Regulation of calcium homeostasis is complex, with several cellular mechanisms operating to control its influx, sequestration, compartmentalization, and efflux. As a result there are several potential targets in the Ca ²⁺ cascade that could be exploited for pharmacological intervention following TBI. For example, one could target calcium-dependent mechanisms regulating glutamate release, or various signaling cascades involving calcium including activation of calpains, caspases, and the mitochondrial permeability transition pore. However, blocking important calcium-mediated regulatory pathways necessary for normal cellular function can also be toxic to the cell in physiological conditions let alone pathological. An additional concern is that improving overall cell viability after TBI by manipulating downstream calcium signaling may simply result in greater numbers of surviving but dysfunctional cells. Finally, due to the complexity of calcium signaling mechanisms, blocking a single calcium-dependent pathway after TBI, particularly downstream, once multiple pathways have been activated, may not be sufficient to prevent other calcium-activated mechanisms from producing secondary cell injury. Therefore, targeting a mechanism that can both decrease glutamate release, and also limit [Ca ²⁺ ] _i accumulation, without completely inhibiting neuronal transmission, has the potential to improve neuronal viability while also preserving the function of the cells. In this review we argue that manipulation of VGCCs may be a rational strategy to achieve this goal.

Voltage-Gated Calcium Channels

VGCCs ( Fig. 11.2 ) are heteromultimers formed by four subunits including a single α ₁ subunit, which incorporates the conduction pore, the voltage sensor, and the gating apparatus, and a combination of three auxiliary subunits α ₂ -δ, β, and γ ( ) each of which modifies the properties of the VGCC ( ). The α ₁ subunit contains four homologous domains each with six transmembrane helical segments (S1–S6) ( ). The S4 segment functions as the voltage sensor and ion selectivity and conductance is determined by the S5 and S6. There are 10 characterized α ₁ subunits that are associated with six classes of VGCCs ( ). There is also evidence that splice variants of the L- ( ) and N-type ( ) VGCC influence the affinity and sensitivity of channels to specific antagonists.