title: FK506 is neuroprotective in a model of antiretroviral toxic neuropathy.
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.
authors.affiliation: Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Keswani
authors.forename: Bani
authors.initials: B
authors.lastname: Chander
authors.forename: Chiler
authors.initials: C
authors.lastname: Hasan
authors.forename: John W
authors.initials: JW
authors.lastname: Griffin
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D015658:HIV Infections / Q000150:complications*; D008928:Mitochondria / Q000502:physiology; D009475:Neurons, Afferent / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000821:virology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012583:Schwann Cells / Q000166:cytology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D018894:Reverse Transcriptase Inhibitors; D016559:Tacrolimus