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Papers: 16 May 2020 - 22 May 2020

Animal Studies, Pharmacology/Drug Development

2020 May 13

Eur J Pharmacol

The isoform-specific functions of the c-Jun N-terminal kinase (JNK) in a mouse model of antiretroviral-induced painful peripheral neuropathy.


Sanna M D, Manassero G, Vercelli A, Herdegen T, Galeotti N
Eur J Pharmacol. 2020 May 13:173161.
PMID: 32416188.


Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with the development of painful neuropathies and may further aggravate sensory neuropathy produced by HIV-1 infection, leading to discontinuation of NRTI therapy by HIV patients. Following antiretroviral-induced peripheral neuropathy, c-Jun N-terminal kinase (JNK) is activated in the dorsal root ganglia (DRG) and spinal cord. However, the contribution of individual JNK genes remains unknown. Here, we have tested the behavioural mechanical sensitivity of JNK1, JNK2 and JNK3 knockout (KO) mice in the von Frey test after treatment with 2',3'-dideoxycytidine (ddC). Protein expression was investigated in the spinal cord of wild type (wt) and KO mice by western blotting. The onset of neuropathic pain was prevented by the deletion of JNK3, leading us to hypothesize that JNK3 protein plays a major role in the regulation of pain threshold in antiretroviral neuropathy. The growth-associated protein 43 (GAP-43) and the transcription factor c-Jun are involved in regeneration processes. This study revealed an up-regulation of GAP-43 and c-Jun protein, 14 days after ddC administration. JNK1 deletion induced a significant reduction in c-Jun phosphorylation and GAP-43 protein contents. In contrast, there was no difference in ddC-induced reduction of hind paw intraepidermal nerve fibre density in all JNK KO mice. Overall, these findings indicate that JNK3 plays a critical role in regulating ddC neurotoxicity-induced mechanical pain hypersensitivity, while JNK1 is important for activation of c-Jun and GAP-43 as a critical pathway of a regeneration program. These data highlight the impact of individual JNK isoforms on antiretroviral neurotoxicity and neuro-regeneration processes.