Omega-3 Polyunsaturated Fatty Acids Alleviate Traumatic Brain Injury by Regulating the Glymphatic Pathway in Mice

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 3 H-mannitol and 14 C-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.

Glymphatic System a Window on TBI Pathophysiology: A Systematic Review

“…In light of these results, an attractive therapeutic approach could be the restoration of the polarization of the AQP4 channels. Zhang et al [ 48 ] found that omega-3 intake could represent a potential therapeutic approach for astroglial alterations following a TBI, as administering fish oil for a period of two months before determining a TBI significantly improves the neuronal function in mouse models, favors the clearance of radiolabeled tracers, and prevents the accumulation of Aß by partially restoring the expression and depolarization of AQP4 impaired by TBI.…”

“…Preclinical studies conducted on mouse models have shown that TBI is able to determine neurological and behavioral alterations such as alterations in consciousness, cognitive functions, coordination, and spontaneous locomotor activity [ 43 , 44 , 46 , 48 , 52 ]. These pathological expressions are probably related to the accumulation of neurotoxic substances due to the altered lymphatic influx/outflow related to the trauma and the consequent neuroinflammation.…”

17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

“…Modified neurological severity score (mNSS) was used to determine the extent of neurological deficits, with 13–18 points reflecting severe abnormality, 7–12 points reflecting moderate abnormality, 1–6 points reflecting mild abnormality, and 0 points reflecting normal function ( Kuramoto et al, 2019 ; Xu et al, 2017 ; Zhang et al, 2020 ). The score system included six subtests: spontaneous movement (0–3), limb symmetry (0–3), forward extension (0–3), climbing (0–3), body proprioception (0–3), and response to tentacles (0–3), with 0 for no abnormality, 1 for mild abnormality, 2 for moderate abnormality, and 3 for severe abnormality.…”

Achieving brain clearance and preventing neurodegenerative diseases—A glymphatic perspective

“…100 PUFAs have recently been suggested to support glymphatic function as mice on a high PUFA diet showed increased CSF tracer influx and clearance, supporting the role of PUFAs in maintaining normal glymphatic function. 101,102 Furthermore, transgenic mice expressing increased levels of omega 3 fatty acids in the brain showed protection against neuronal death from increased levels of amyloid beta. 101 Interestingly, this protective effect was not seen in AQP4 knockout mice where the glymphatic system was inhibited.…”