NPD1/GPR37 axis protects painful traumatic brain injury and its complications

Abstract

AbstractPatients with traumatic brain injury (TBI) frequently exhibit heightened pain and associated complications such as cognitive decline, depression, and anxiety. GPR37 is widely expressed in various brain regions, but its function remains largely unclear. We recently discovered neuroprotectin D1 (NPD1) as a novel GPR37 ligand. In this study, we examined the protective role of the NPD1/GPR37 signaling pathway in TBI-induced neuropathic pain and its complications. TBI was induced by closed-head impact and resulted in transient neuropathic pain for less than two weeks, showing periorbital and cutaneous mechanical allodynia/hyperalgesia, as well as motor deficiency and cognitive impairment. We found that peri-surgical treatment with NPD1, effectively prevented TBI-induced mechanical hypersensitivity, motor deficiency, and cognitive impairment. NPD1 treatment also substantially inhibited TBI-induced microgliosis, astrogliosis (including A1 astrocyte markers), and neuroinflammation in the sensory cortex and hippocampus. RNA sequencing and GO enrichment analysis revealed downregulations of genes related to “calcium ion homeostasis,” and “GPCR signaling pathway” in the TBI-affected brain. These downregulations were restored by NPD1 treatment. RNAscopein situhybridization revealed predominantGpr37mRNA expression in oligodendrocytes. TBI resulted in rapid and remarkable demyelination and downregulation ofGpr37mRNA expression in oligodendrocytes, and both were protected by NPD1 treatment. NPD1’s inhibition of periorbital and cutaneous mechanical pain was abolished inGpr37-/-mice. Moreover, TBI-induced neuropathic pain was prolonged by swimming stress, and NPD1 treatment prevented the stress-induced transition from acute to chronic pain in wild-type mice but notGpr37-/-mice. Finally, chronic pain was associated with depression and anxiety, and NPD1 treatment mitigated these chronic pain complications through GPR37. Thus, through modulation of demyelination, diverse responses of glial cells, and neuroinflammation, the NPD1/GPR37 axis serves as a protective mechanism and a therapeutic target against painful traumatic brain injury and its complications.