Abstract
Background: The glymphatic pathway has been shown to be impaired in traumatic brain injury (TBI). Omega-3 polysaturated fatty acids (Omega-3, PUFAs) are involved in the clearance of amyloid-ß through the glymphatic system and this effect is Aquaporin-4 (AQP4) dependent. We hypothesize that Omega-3 PUFAs can alleviate neurological impairment in TBI by protecting the glymphatic pathway.Methods: We pretreated mice with Omega-3 PUFAs rich fish oil and introduced TBI in the mice. Neurological functions were assessed through the modified neurological severity score (mNSS) system and Rota-rod test. Aß42 levels and radioisotope clearance were examined to determine the function of glymphatic system. AQP4 protein and mRNA expressions and its polarity were examined in fish oil treated TBI mice or control mice. Finally, the integrity of blood-brain barrier was determined by Evans blue extravasation and measurement of tight junction proteins (ZO-1 and Occludin) levels.Results: TBI surgery induced significant neurological functional impairment, Omega-3 PUFAs attenuated TBI-induced neurological impairment, as evidenced by reduced mNSS, improved performance in the Rota-rod test. Furthermore, Omega-3 PUFAs improved glymphatic clearance after induction of TBI in mice, reduced Aß42 accumulation, partially restored the clearance of both 3H-mannitol and 14C-Inulin. Omega-3 PUFAs also suppressed AQP4 expression and partially prevented loss of AQP4 polarity in mice undergoing TBI. Finally, Omega-3 PUFAs protected mice from TBI induced blood-brain barrier disruption.Conclusion: Omaga-3 PUFAs attenuate neurological function by partially restoring the AQP4 dependent glymphatic system in mice with TBI.
Highlights
A recently identified system for clearance of waste substances in the brain, the glymphatic system eliminates harmful metabolites and soluble proteins from the central nervous system and mediates distribution of neuromodulators, growth factors, and other compounds throughout the brain through perivascular passages composed of astrocytes [1]
To confirm the enrichment of fatty acids in mice treated with fish oil, we assessed fatty acid profile in the brain before the induction of traumatic brain injury (TBI) through capillary gas chromatography as described previously [17] (Supplementary Figure 1). We found that both groups had similar levels of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) and that mice treated with fish oil had significantly reduced Omega-6 PUFA and significantly increased Omega-3 PUFAs compared to that of the control group (Supplementary Figure 1a)
Among the Omega-3 PUFAs, we found that fish oil treatment significantly increased the levels of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA), and not α-linolenic acid (ALA) (Supplementary Figure 1c)
Summary
A recently identified system for clearance of waste substances in the brain, the glymphatic system eliminates harmful metabolites and soluble proteins from the central nervous system and mediates distribution of neuromodulators, growth factors, and other compounds throughout the brain through perivascular passages composed of astrocytes [1]. Disruption of the glymphatic system has been shown to mediate chronic traumatic encephalopathy and brain trauma [2]. This perivascular pathway exerts its function by facilitating the exchange of cerebrospinal fluid (CSF) and the interstitial fluid (ISF) [3]. Perturbation of AQP4 expression or disruption in the polarity of the AQP4 protein leads to glymphatic dysfunction, which have been shown in several neurological diseases including stroke, Alzheimer’s disease and traumatic brain injury (TBI) [7]. The glymphatic pathway has been shown to be impaired in traumatic brain injury (TBI). Omega-3 polysaturated fatty acids (Omega-3, PUFAs) are involved in the clearance of amyloid-ß through the glymphatic system and this effect is Aquaporin-4 (AQP4) dependent. We hypothesize that Omega-3 PUFAs can alleviate neurological impairment in TBI by protecting the glymphatic pathway
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