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FK506 is neuroprotective in a model of antiretroviral toxic neuropathy
Author(s) -
Keswani Sanjay C.,
Chander Bani,
Hasan Chiler,
Griffin John W.,
McArthur Justin C.,
Hoke Ahmet
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10401
Subject(s) - neurotoxicity , neuroprotection , peripheral neuropathy , medicine , calcineurin , pharmacology , immunology , toxicity , transplantation , diabetes mellitus , endocrinology
Abstract Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus–infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC‐induced “neuritic pruning,” neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin‐independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy. Ann Neurol 2003;53:000–000