Selective inhibition of histone deacetylase 3 (HDAC3) prevents vincristine-induced peripheral neuropathy via macrophage polarization

Neuroinflammation is vital in vincristine-induced peripheral neuropathy (VIPN). Locally infiltrated macrophages polarize to pro-inflammatory M1-type, release inflammatory cytokines, and contribute to neuropathic pain. Histone deacetylase 3 (HDAC3) regulates macrophage polarization. In a mouse model of VIPN (0.5 mg/kg vincristine, i.p.), we observed increased HDAC3 activity in dorsal root ganglia (DRG). Therefore, we hypothesized that the selective HDAC3 inhibitor, PT3, would polarize macrophages from pro-inflammatory M-1 to anti-inflammatory M-2, reducing the inflammation-induced neuropathic pain in VIPN. Interestingly, co-treatment of vincristine and PT3 (15 mg/kg, i.p.) prevented the development of vincristine-induced mechanical allodynia and thermal hyperalgesia as assessed by pin-prick and hot plate methods, respectively. PT3 also preserved the sensory nerve conduction and reduced the loss of PGP9.5-positive intraepidermal nerve fibers in the paw skin. Additionally, vincristine-induced motor dysfunction, as assessed by open field test, paw print analysis, and motor nerve conduction studies, was also alleviated by HDAC3 inhibition. To investigate the underlying mechanism, we utilized immunoblotting and immunohistochemistry to determine the population of M1 and M2 macrophages using specific markers. We observed that the co-treatment with PT3 significantly reduced the number of infiltrated M1 macrophages (CD80⁺) and increased M2 macrophages (CD163+) in the sciatic nerves compared to the vincristine-treated group. Moreover, the quantitative cytokine profile revealed reduced expression of pro-inflammatory cytokines (IL-6, TNF-α) and increased expression of anti-inflammatory cytokine (IL-10) in both the sciatic nerve and DRG from the PT3-treated compared to the vincristine-treated group. Collectively, our data strongly demonstrated that selective HDAC3 inhibition is a promising target for the amelioration of VIPN.