Neuroprotective and neuroregenerative effects of new TSPO ligands in the peripheral nervous system

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TSPO has been identified as an effective pharmacological target for protecting neurons and for increasing the speed of axonal regrowth in the peripheral nervous system. Agonistic ligands of TSPO therefore offer promising therapeutic perspectives for promoting peripheral nerve regeneration after traumatic injury or in patients with peripheral neuropathies. As part of a large mitochondrial membrane protein complex TSPO regulates many mitochondrial activities. Its best characterized function is the intramitochondrial transport of cholesterol, a rate-limiting step in steroid synthesis. However, the precise role of steroids in mediating the regenerative effects of TSPO ligands remains to be determined.Grünenthal has developed new potent TSPO activators, which improve functional regeneration of both sensory neurons and motoneurons and prevent the development of neuropathic pain after severe peripheral nerve injury. These particularly efficient compounds are in fact dual-target ligands, as they activate both TSPO and voltage-gated delayed-rectifier potassium channels of the Kv7 family. These ion channels are involved in the regulation of neuronal excitability and play a role in the development of neuropathic pain. This has led to the hypothesis that the co-activation of both TSPO and Kv7 channels may be additive, or even reinforce the pharmacological effects of the individual mechanisms.Our objectives are to experimentally test this dual-activation hypothesis and to clarify the role of steroids in the neuroprotective and neuroregenerative efficacy of TSPO activation. To reach these aims we have set up experimental rat models of severe crush injury of cervical spine nerves and of the sciatic nerve. Moreover, we will use transgenic, pharmacological and biochemical tools. The respective contribution of TSPO and Kv7 channel activation in the curative potential of the Grünenthal compounds can be investigated due to the advent of TSPO knockout rats and the availability of selective TSPO and Kv7 ligands. The importance of TSPO-stimulated steroid synthesis will be studied by using selective and potent inhibitors of steroidogenic enzymes and steroid receptors. Changes in peripheral nerve steroid levels will be analyzed by gas chromatography-tandem mass spectrometry (GC-MS/MS). This technology has become a reference method for the specific, sensitive and robust analysis of steroids in small biological samples. Our GC-MS/MS platform will therefore become a centralized facility for steroid analysis for the whole research unit.Promoting neuroprotection and neuroregeneration corresponds to an unmet medial need. The delineation of TSPO in combination with Kv7 channel activation may constitute a novel therapeutic approach for peripheral nerve lesions and for peripheral axonopathies, including diabetic and toxic neuropathies, which all are characterized by a reduced regenerative capacity.