Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders

• Published in: Expert opinion on investigational drugs Vol. 9; no. 10; p. 2331
• Main Author: Gold, B G
• Format: Journal Article
• Language: English
• Published: England 01.10.2000
• Subjects: Animals; Brain Injuries - drug therapy; Carpal Tunnel Syndrome - drug therapy; Cyclosporine - pharmacology; Cyclosporine - therapeutic use; Humans; Immunophilins - pharmacology; Immunophilins - therapeutic use; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Ligands; Nerve Regeneration - drug effects; Nerve Regeneration - physiology; Nervous System Diseases - drug therapy; Spinal Cord Injuries - drug therapy; Tacrolimus - chemistry; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Tacrolimus Binding Protein 1A - drug effects; Tacrolimus Binding Protein 1A - physiology
• ISSN: 1354-3784; 1744-7658
• DOI: 10.1517/13543784.9.10.2331

Neuroimmunophilin ligands are a class of compounds that hold great promise for the treatment of nerve injuries and neurological disease. In contrast to neurotrophins (e.g., nerve growth factor), these compounds readily cross the blood-brain barrier, being orally effective in a variety of animal models of ischaemia, traumatic nerve injury and human neurodegenerative disorders. A further distinction is that neuroimmunophilin ligands act via unique receptors that are unrelated to the classical neurotrophic receptors (e.g., trk), making it unlikely that clinical trials will encounter the same difficulties found with the neurotrophins. Another advantage is that two neuroimmunophilin ligands (cyclosporin A and FK-506) have already been used in humans (as immunosuppressant drugs). Whereas both cyclosporin A and FK-506 demonstrate neuroprotective actions, only FK-506 and its derivatives have been clearly shown to exhibit significant neuroregenerative activity. Accordingly, the neuroprotective and neuroregenerative properties seem to arise via different mechanisms. Furthermore, the neuroregenerative property does not involve calcineurin inhibition (essential for immunosuppression). This is important since most of the limiting side effects produced by these drugs arise via calcineurin inhibition. A major breakthrough for the development of this class of compounds for the treatment of human neurological disorders was the ability to separate the neuroregenerative property of FK-506 from its immunosuppressant action via the development of non-immunosuppressant (non-calcineurin inhibiting) derivatives. Further studies revealed that different receptor subtypes, or FK-506-binding proteins (FKBPs), mediate immunosuppression and nerve regeneration (FKBP-12 and FKBP-52, respectively, the latter being a component of steroid receptor complexes). Thus, steroid receptor chaperone proteins represent novel targets for future drug development of novel classes of compounds for the treatment of a variety of human neurological disorders, including traumatic injury (e.g., peripheral nerve and spinal cord), chemical exposure (e.g., vinca alkaloids, Taxol) and neurodegenerative disease (e.g. , diabetic neuropathy and Parkinson's disease).