Brain Advance Access originally published online on July 6, 2007
Brain 2007 130(8):2011-2023; doi:10.1093/brain/awm148
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression
Departments of 1Medicine and 3Medical Genetics, University of Alberta, Edmonton AB, Canada T6G 2S2, 2Department of Clinical Neuroscience, University of Calgary, Calgary AB, Canada T2N 4N1 and 4Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Correspondence to: Dr C. Power, Department of Medicine, 611 Heritage Medical Research Centre, University of Alberta, Edmonton AB, Canada T6G 2S2 E-mail: chris.power{at}ualberta.ca
Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developed ex vivo and in vivo models of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons. We investigated neuronal morphology, neurobehavioural testing, viral load, mitochondrial and neurotrophic factor gene expression after ddI treatment of FIV-infected and uninfected animals or dorsal root ganglia (DRG) cultures. ddI caused concentration-dependent neuronal injury in cultured feline DRGs (P < 0.05), together with reduced viral replication and diminished expression of mitochondrial cytochrome C oxidase subunit I gene (mtCOX I) and the neurotrophin, brain-derived neurotrophic factor (BDNF). Indeed, BDNF treatment reversed neuronal injury caused by FIV infection in the presence or absence of ddI exposure (P < 0.05). In vivo FIV infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddI treatment. Epidermal density of nerve endings was reduced after FIV infection (P < 0.05), especially with ddI treatment. Although viral replication in blood was suppressed in ddI-treated animals (P < 0.05), ddI had a limited effect on viral abundance in DRGs of the same animals. ddI decreased mtCOX I expression in DRG neurons of FIV-infected animals (P < 0.05). BDNF expression was downregulated by ddI in DRG Schwann cells following FIV infection. Thus, ddI treatment during FIV infection resulted in additive pathogenic effects contributing to the development of ATN, which was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in DRGs, highlighting the convergent pathogenic effects that antiretroviral drugs might have in patients with HIV infection.
Key Words: HIV; FIV; didanosine; BDNF; mitochondria; neuropathy
Abbreviations: ATN, antiretroviral toxic neuropathy; ddI, didanosine; FIV, feline immunodeficiency virus; DRG, dorsal root ganglion; NGS, normal goat serum
Received February 13, 2007. Revised May 23, 2007. Accepted May 30, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C-C Chao, H-Y Sun, Y-C Chang, and S-T Hsieh Painful neuropathy with skin denervation after prolonged use of linezolid J. Neurol. Neurosurg. Psychiatry, January 1, 2008; 79(1): 97 - 99. [Abstract] [Full Text] [PDF]
|
|