A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

Abstract

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 hours after 60 minutes of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

Effect of a multinutrient intervention after ischemic stroke in female C57Bl/6 mice

“…Furthermore, in several brain areas, WM and GM integrity of the Fortasyn mice was higher than in the Control mice. These beneficial effects of Fortasyn are in line with previous studies testing the effect of (components of) this multinutrient intervention on brain integrity (Jiang et al 2016;Wiesmann et al 2016) and they are furthermore supportive of the membrane synthesizing potential of this particular multinutrient intervention (van Wijk et al 2014). Up to now, mechanisms are still unknown how tissue integrity could be influenced by dietary components like omega-3 fatty acids.…”

“…As stroke-induced WM impairments can cause sensorimotor impairments (Wang et al 2016), the improved performance in the PPI test by Fortasyn-treated mice may be linked to the rescue of WM integrity by this diet. Indeed, in mice treated with n-3 polyunsaturated fatty acids, improvements in WM integrity were positively correlated with sensorimotor performance in the cylinder test (Jiang et al 2016). The beneficial effect of Fortasyn on sensorimotor integration in this study may be indicative of the efficacy of multinutrient interventions in psychiatric disorders with extensive sensorimotor impairments, such as schizophrenia and Gilles de la Tourette's syndrome (Geyer 2006;Kohl et al 2013).…”

“…Indeed, in mice treated with n‐3 polyunsaturated fatty acids, improvements in WM integrity were positively correlated with sensorimotor performance in the cylinder test (Jiang et al . ). The beneficial effect of Fortasyn on sensorimotor integration in this study may be indicative of the efficacy of multinutrient interventions in psychiatric disorders with extensive sensorimotor impairments, such as schizophrenia and Gilles de la Tourette's syndrome (Geyer ; Kohl et al .…”

“…These beneficial effects of Fortasyn are in line with previous studies testing the effect of (components of) this multinutrient intervention on brain integrity (Jiang et al . ; Wiesmann et al . ) and they are furthermore supportive of the membrane synthesizing potential of this particular multinutrient intervention (van Wijk et al .…”

Repetitive and Prolonged Omega-3 Fatty Acid Treatment after Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery

“…Another important restorative mechanism is oligodendrogenesis, which is essential for remyelination and white matter repair after TBI 49 . Following ischemic brain injury, delayed n-3 PUFA administration is capable of promoting angiogenesis and oligodendrogenesis, which are associated with improved functional recovery 50,51 . In the present study, we noticed an enhancement of post-TBI angiogenesis and oligodendrogenesis upon n-3 PUFA treatment that lasted up to 35 days after injury.…”