The non-genomic action of histone deacetylase 5 in astrocytes in painful diabetic neuropathy

Abstract

Diabetes mellitus is a modern global medical challenge, and it is estimated that approximately 366 million patients will have diabetes in 2030. Painful diabetic neuropathy (PDN) is one of the most common complications of diabetes, affecting a quarter of diabetic patients. It is urgent to elucidate the mechanistic targets of PDN for safer and more effective therapies. Although primary afferent nerve damage and peripheral sensitization are considered the principal mechanism of PDN, accumulating evidence implicates that central sensitization is also critical in maintaining PDN. In the central nervous system (CNS), the role of neurons in pain modulation has been well investigated. In recent years, non-neuronal cells such as astrocytes have been suggested as critical regulators involved in the central sensitization mechanisms of neuropathic pain. Moreover, epigenetic regulations have been reported to play a pivotal role in developing nociceptive hypersensitivity. Therefore, this thesis investigates whether changes of astrocytes regulated by epigenetics are involved in PDN. In Chapter 2, the current thesis demonstrates the dysfunction and morphological atrophy of astrocytes involved in maintaining PDN, which may occur before neuron death. Next, this study explores the mechanisms of astrocytes changes. HDAC5, as the class II family member, performs the deacetylation function on histone and non-histone proteins. The role of HDAC5 in non-histone protein was discussed in this thesis. HDAC5 removes the acetyl group from the non-histone protein STAT3. It is well known that acetylated STAT3 is critical for STAT3 dimerization and its translocation to the nuclear, facilitating binding to the promoter of target genes. Thus, the hypoacetylation of STAT3 mediated HDAC5 impairs the transcriptional activity of STAT3, which represses the expression of GFAP. Consequently, the deacetylation of STAT3 mediated by HDAC5 contributes to morphological and functional changes of astrocytes in PDN. Moreover, overexpression of STAT3 or knocking down HDAC5 expression can restore the morphology and function of astrocytes and improve PDN in diabetic rats induced by STZ. The involvement of HDAC5-STAT3-GFAP axis signaling provides novel and promising therapeutic targets to counteract PDN induced by STZ. Mounting evidence has suggested that neuroinflammation in the peripheral nervous system (PNS) and central nervous system (CNS) play an essential role in neuropathic pain. Many cytokines and chemokines are released during neuroinflammation, contributing to neurotoxicity and neuronal death. In Chapter 3, the expression of cytokines TNF-α and chemokines (CXCL12) receptor CXCR4 are investigated in the PNS (DRG) and CNS (spinal cord). This study indicates that the neuroinflammation in DRG contributes to the initial stage of PDN. Moreover, upregulation of pro-inflammatory protein TNF-a and CXCR4 in the spinal cord may play a critical role in the late phase of PDN. Collectively, the progressive increase of TNF-a and CXCR4 expression in the dorsal root ganglia (DRG) and spinal cord contributed to PDN induced by STZ. The peripheral neuroinflammation and central neuroinflammation are evoked at different periods in the progression of PDN.