Blockade of Presynaptic α2δ1−2 Subunits of Voltage-Gated Ca²⁺ Channels Attenuates Neurobiochemical and Sensorimotor Deficits After Traumatic Brain Injury in Mice

TL;DR

Blocking presynaptic α2δ1-2 subunits with pregabalin reduces brain injury effects in mice, improving neurological and motor outcomes.

Contribution

Demonstrates that targeting presynaptic α2δ1-2 subunits mitigates TBI-induced neurodegeneration and sensorimotor deficits in mice.

Findings

Pregabalin reduced glutamate levels and improved mitochondrial calcium handling after TBI.

Treatment decreased neurodegeneration markers like caspase-3 and Tau hyperphosphorylation.

Pregabalin improved sensorimotor function and neurological severity scores in injured mice.

Abstract

Traumatic brain injury (TBI) to the motor cortex disrupts corticospinal tracts and induces persistent sensorimotor impairments, largely driven by secondary neurobiochemical cascades. Excessive synaptic glutamate release, mitochondrial Ca²⁺ overload, and progressive neurodegeneration critically shape these outcomes, with preclinical and clinical data revealing neuronal loss and proteinopathy resembling motor neuron disorders. Here, we investigated whether pregabalin blockade of the presynaptic α2δ1-2 subunit of voltage-gated Ca²⁺ channels could mitigate excitotoxicity and promote sensorimotor recovery after TBI. Mice subjected to controlled cortical impact (CCI) received daily pregabalin (i.p., 60 mg.kg-1) or saline for 10 days, and neurobehavioral performance was assessed at 24 h, 11-, and 12-days post-injury. In addition to robust and persistent deficits detected by the modified neurological severity score (mNSS), complementary tests including open field, grip strength, cylinder, wire-hanging, and inverted screen, captured sensitive impairments in corticospinal integrity and global motor function. Pregabalin treatment downregulated α2δ2 subunit expression, reduced cerebrospinal fluid glutamate levels, and restored mitochondrial Ca²⁺ handling by improving influx–efflux dynamics through Na⁺/Ca²⁺ exchange. At the molecular level, pregabalin decreased hallmarks of neurodegeneration, including Cyclin dependent kinase 5, TauSer396 hyperphosphorylation, caspase-12, and caspase-3 within synaptic terminals. These neuroprotective effects translated into significant improvements in both mNSS and multidimensional sensorimotor outcomes following TBI. Together, our findings confirm the neurodegenerative trajectory underlying TBI-induced neuromotor deficits and highlight the presynaptic α2δ1–2 subunit antagonism as a promising therapeutic target to mitigate long-term neurological sequelae.

The online version contains supplementary material available at 10.1007/s11064-026-04729-3.

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