GRT-X Stimulates Dorsal Root Ganglia Axonal Growth in Culture via TSPO and Kv7.2/3 Potassium Channel Activation.

GRT-X, which targets both the mitochondrial translocator protein (TSPO) and the Kv7.2/3 (KCNQ2/3) potassium channels, has been shown to efficiently promote recovery from cervical spine injury. In the present work, we investigate the role of GRT-X and its two targets in the axonal growth of dorsal root ganglion (DRG) neurons. Neurite outgrowth was quantified in DRG explant cultures prepared from wild-type C57BL6/J and TSPO-KO mice. TSPO was pharmacologically targeted with the agonist XBD173 and the Kv7 channels with the activator ICA-27243 and the inhibitor XE991. GRT-X efficiently stimulated DRG axonal growth at 4 and 8 days after its single administration. XBD173 also promoted axonal elongation, but only after 8 days and its repeated administration. In contrast, both ICA27243 and XE991 tended to decrease axonal elongation. In dissociated DRG neuron/Schwann cell co-cultures, GRT-X upregulated the expression of genes associated with axonal growth and myelination. In the TSPO-KO DRG cultures, the stimulatory effect of GRT-X on axonal growth was completely lost. However, GRT-X and XBD173 activated neuronal and Schwann cell gene expression after TSPO knockout, indicating the presence of additional targets warranting further investigation. These findings uncover a key role of the dual mode of action of GRT-X in the axonal elongation of DRG neurons.

The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.

Translocator protein (TSPO, 18 kDa), formerly known as peripheral benzodiazepine receptor, is an evolutionary well-conserved protein located on the outer mitochondrial membrane. TSPO is involved in a variety of fundamental physiological functions and cellular processes. Its expression levels are regulated under many pathological conditions, therefore, TSPO has been proposed as a tool for diagnostic imaging and an attractive therapeutic drug target in the nervous system. Several synthetic TSPO ligands have thus been explored as agonists and antagonists for innovative treatments as neuroprotective and regenerative agents. In this review, we provide state-of-the-art knowledge of TSPO functions in the brain and peripheral nervous system. Particular emphasis is placed on its contribution to important physiological functions such as mitochondrial homeostasis, energy metabolism and steroidogenesis. We also report how it is involved in neuroinflammation, brain injury and diseases of the nervous system.