TSPO Ligand 2-Cl-MGV-1 Mitigates Traumatic Brain Injury (TBI) in a Mouse Model

In this study, we assessed the ability of 2-Cl-MGV-1 (2-chlorophenyl quinazolin-4-yl, dimethyl carbamate), a ligand of the 18 kDa mitochondrial translocator protein (TSPO), to mitigate brain damage in a mouse model of traumatic brain injury (TBI). TSPO is important for arresting the death of neurons and glia and counteracting microglial activation, and it provides anti-inflammatory activity, promotes regeneration (including neurons), and contributes to angiogenesis. We assessed the minimal dose of the TSPO ligand 2-Cl-MGV-1 that attenuates the magnitude of brain damage as well as the time window following TBI in which the treatment is effective. We found that 7.5 mg/kg of 2-Cl-MGV-1 can reduce the impact of the TBI as assessed by magnetic resonance imaging (MRI). We also found that 2-Cl-MGV-1 improved motor performance as observed in a treadmill test (80.9% fewer shocks needed and 40.7% more distance covered, both <i>p</i> < 0.05), and reduced anatomical brain damage (by 86.5%, <i>p</i> < 0.05), cell death (by 75.0%, <i>p</i> < 0.001), and microglial inflammatory response (by 50.2%, <i>p</i> < 0.01). The treatment also increased expression of neuronal markers NeuN and β3-tubulin (30.0%, <i>p</i> < 0.01; 36.0%, <i>p</i> < 0.01, respectively). The time window in which we found the treatment to be effective was 3-11 h after TBI. Our study suggests that agents active at the TSPO can significantly attenuate the outcome of TBI, including in the structural, cellular, and neuro-behavioral dimensions. The mechanisms involved in the attenuation of brain damage following TBI may be related to a decrease in cell death and to anti-inflammatory activity. TSPO seems to be a novel target for the development of agents aimed at the suppression of neurodegenerative processes.