title: PKC-mediated HuD-GAP43 pathway activation in a mouse model of antiretroviral painful neuropathy.
abstract: Patients treated with nucleoside reverse transcriptase inhibitors (NRTIs) develop painful neuropathies that lead to discontinuation of antiretroviral therapy thus limiting viral suppression strategies. The mechanisms by which NRTIs contribute to the development of neuropathy are not known. In order to elucidate the mechanisms underlying this drug-induced neuropathy, we have characterized cellular events in the central nervous system following antiretroviral treatment. Systemic administration of the antiretroviral agent, 2',3'-dideoxycytidine (ddC) considerably increased the expression and phosphorylation of protein kinase C (PKC) γ and ɛ, enzymes highly involved in pain processes, within periaqueductal grey matter (PAG), and, to a lesser extent, within thalamus and prefrontal cortex. These events appeared in coincidence with thermal and mechanical allodynia, but PKC blockade did not prevent the antiretroviral-induced pain hypersensitivity, ruling out a major involvement of PKC in the ddC-induced nociceptive behaviour. An increased expression of GAP43, a marker of neuroregeneration, and decreased levels of ATF3, a marker of neuroregeneration, were detected in all brain areas. ddC treatment also increased the expression of HuD, a RNA-binding protein target of PKC known to stabilize GAP43 mRNA. Pharmacological blockade of PKC prevented HuD and GAP43 overexpression. Silencing of both PKCγ and HuD reduced GAP43 levels in control mice and prevented the ddC-induced GAP43 enhanced expression. Present findings illustrate the presence of a supraspinal PKC-mediated HuD-GAP43 pathway activated by ddC. Based on our results, we speculate that antiretroviral drugs may recruit the HuD-GAP43 pathway, potentially contributing to a response to the antiretroviral neuronal toxicity.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of, Psychology, Drug, Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: M D
authors.initials: MD
authors.lastname: Sanna
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Quattrone
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of, Psychology, Drug, Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of, Psychology, Drug, Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy. Electronic address: nicoletta.galeotti@unifi.it.
authors.forename: N
authors.initials: N
authors.lastname: Galeotti
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism*; D000067779:ELAV-Like Protein 4; D019922:GAP-43 Protein / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D016047:Zalcitabine / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498011:Elavl4 protein, mouse; D019922:GAP-43 Protein; D018894:Reverse Transcriptase Inhibitors; D016047:Zalcitabine; D011493:Protein Kinase C
keywords: 1,2-Dioleoyloxy-3-(trimethylammonium)propane (PubChem CID: 6437371); 2′,3′-Dideoxycytidine (PubChem CID: 24066); Amitriptyline (PubChem CID: 11065); Antiretroviral; Calphostin C (PubChem CID: 2533); Dimethyl sulfoxide (PubChem CID: 679); GAP-43; Gabapentin (PubChem CID: 3446); HuD; Leupeptin (PubChemCID: 72429); Neuropathy; Neuroregeneration; Phenylmethylsulfonyl fluoride (PubChem CID: 4784); Protein kinase C; Sodium orthovanadate (PubChem CID: 61671)