KDM4A facilitates neuropathic pain and microglial M1 polarization by regulating BDNF in a rat model of brachial plexus avulsion

BACKGROUND: Many patients with brachial plexus avulsion (BPA) suffer from neuropathic pain, but the mechanism remains elusive. Modifications of histones, the proteins responsible for organizing DNA, may play an important role in neuropathic pain. Lysine demethylase 4A (KDM4A), an essential component of histone demethylase, can modify the function of chromatin and thus regulate the vital gene expressions. However, the mechanism by which KDM4A regulates neuropathic pain following BPA remains unclear. METHODS: The pain model was developed in adult rats that received BPA surgery. Western blot, ELISA, and reverse transcription-PCR were used to examine the protein and mRNA levels of targeted genes. Immunofluorescence studies were conducted to analyze their cellular distribution in the spinal cord. Pharmacological and genetic methods were used to modulate the expression of KDM4A. Co-immunoprecipitation and chromatin immunoprecipitation PCR were used to assess the binding potential between KDM4A and the promoter of brain-derived neurotrophic factor (BDNF). RESULTS: KDM4A and BDNF levels were significantly upregulated in the ipsilateral spinal cord dorsal horn in the BPA group compared with the sham surgery group. Additionally, knockdown of KDM4A decreased BDNF expression and microgliosis and reduced neuropathic pain-like behaviors in BPA rats. Conversely, KDM4A overexpression increased BDNF expression and microgliosis and exacerbated neuropathic pain. BDNF inhibitors and activators also regulated the activation of spinal microglia and neuropathic pain. Importantly, we showed that KDM4A modulates BDNF expression by regulating the methylation of histone 3 lysine 9 and histone 3 lysine 36 in its promoter region. CONCLUSION: Current findings suggest that the upregulation of KDM4A increases BDNF expression in the spinal cord in rats after BPA, contributing to microgliosis, neuroinflammation, and neuropathic pain.