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

Abstract

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.