TY - JOUR
T1 - Didanosine causes sensory neuropathy in an HIV/AIDS animal model
T2 - Impaired mitochondrial and neurotrophic factor gene expression
AU - Zhu, Yu
AU - Antony, Joseph M.
AU - Martinez, Jose A.
AU - Glerum, D. Moira
AU - Brussee, Valentine
AU - Hoke, Ahmet
AU - Zochodne, Douglas
AU - Power, Christopher
N1 - Funding Information:
The authors thank Kris Ellestad, Serena Viappiani for helpful discussions and Robyn Flynn for technical assistance. These studies were supported by National Institutes of Health (CP) [IR 01NS4626201] and the Canadian Institutes of Health Research (CIHR) (CP). Y.Z. holds a CIHR Fellowship. J.M.A. was supported by a Studentship from the Alberta Heritage Foundation for Medical Research (AHFMR). D.Z. is an AHFMR Scientist, D.M.G. is an AHFMR Senior Scholar and C.P. is an AHFMR Senior Scholar and holds a Canada Research Chair (T1) in Neurological Infection and Immunity.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
KW - BDNF
KW - Didanosine
KW - FIV
KW - HIV
KW - Mitochondria
KW - Neuropathy
UR - http://www.scopus.com/inward/record.url?scp=34547793113&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547793113&partnerID=8YFLogxK
U2 - 10.1093/brain/awm148
DO - 10.1093/brain/awm148
M3 - Article
C2 - 17616550
AN - SCOPUS:34547793113
SN - 0006-8950
VL - 130
SP - 2011
EP - 2023
JO - Brain
JF - Brain
IS - 8
ER -