Scholars@Duke publication: NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain.

NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain.

Publication , Journal Article

Zhao, J; Li, R; Wang, Y; Chandra, S; Zhang, V; Wang, H; Ji, R-R

Published in: Brain Behav Immun

December 10, 2025

Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., Fkbp5). The antinociceptive effects of NPD1 were abolished in Gpr37-/- mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not Gpr37-/- mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.