Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse

Abstract

Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response. Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6-10 min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100ng daily), AT-RvD1 (100ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3 days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24 hours post-injury. For days 1-7 post-injury, motor outcome was assessed by Rotarod. Cognitive function was measured at 6 days post-injury using Novel Object Recognition (NOR). At 7 days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1. In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone.

N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update

“…for 7 days starting 3 days before the percussion reduced the injury induced cognitive impairment and motor deficit, but did not reduce microglia activation. RvE1, however, did reduce traumatic brain injury induced microglia activation, while not having any effects on the cognitive impairments and motor deficits (Harrison et al, 2015).…”

Aging with Traumatic Brain Injury: Effects of Age at Injury on Behavioral Outcome following Diffuse Brain Injury in Rats

“…The righting reflex time is the total time from the initial impact until the rat spontaneously rights itself from a supine position. A righting reflex time of 5-10 min for all age groups was indicative of moderate injury and used as inclusion criteria for the study, as previously published [19,23,24,25,26]. In juvenile rats (PND 17), the presence of a seizure shortened the righting reflex times as juveniles consistently righted themselves immediately following injury-induced seizure.…”

Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid Mediators of Inflammation to Ameliorate the Deleterious Effects of Blast Over Pressure on Eye and Brain Visual Processing Centers in Rats

“…injection (Luo, 2013). Likewise, mice subjected to brain damage by lateral fluid percussion injury (FLPI) showed marked improvements in neuro-behavioral function (e.g., rotarod) and suppressed neuro-inflammation responses (e.g., microglia activation), when intraperitoneal injected with resolvin D1 and resolvin E1 (Harrison, 2015); however, to see this effect, both prophylactic and postinjury administration of the drugs had to be done (i.e., 3 days before and after, at 5 μg/kg). It also must be considered that the brain damage used in the two studies above are more shallow focal point injuries and not of the deep diffusive nature that our blast wave model produces; and thus, they are easier to effectively target and heal.…”