Volume 53, Issue 1 pp. 57-64
Original Articles

FK506 is neuroprotective in a model of antiretroviral toxic neuropathy

Sanjay C. Keswani MBBS, MRCP

Sanjay C. Keswani MBBS, MRCP

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Search for more papers by this author
Bani Chander BS

Bani Chander BS

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Search for more papers by this author
Chiler Hasan MS

Chiler Hasan MS

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Search for more papers by this author
John W. Griffin MD

John W. Griffin MD

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Department of Neuroscience, The Johns Hopkins University, Baltimore, MD

Search for more papers by this author
Justin C. McArthur MBBS, MPH

Justin C. McArthur MBBS, MPH

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Department of Epidemiology, The Johns Hopkins University, Baltimore, MD

Search for more papers by this author
Ahmet Hoke MD, PhD

Corresponding Author

Ahmet Hoke MD, PhD

Department of Neurology, The Johns Hopkins University, Baltimore, MD

Department of Neuroscience, The Johns Hopkins University, Baltimore, MD

Department of Neurology, The Johns Hopkins Hospital, Path 509, 600 North Wolfe Street, Baltimore, MD 21287Search for more papers by this author
First published: 04 December 2002
Citations: 62

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

The full text of this article hosted at iucr.org is unavailable due to technical difficulties.

click me