Abstract
The aged population is among the highest at risk for ischemic stroke, yet most stroke patients of advanced ages (>80 years) are excluded from access to thrombolytic treatment by tissue plasminogen activator, the only FDA approved pharmacological therapy for stroke victims. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) robustly alleviate ischemic brain injury in young adult rodents, but have not yet been studied in aged animals. This study investigated whether chronic dietary supplementation of n-3 PUFAs protects aging brain against cerebral ischemia and improves long-term neurological outcomes. Aged (18-month-old) mice were administered n-3 PUFA-enriched fish oil in daily chow for 3 months before and up to 8 weeks after 45 minutes of transient middle cerebral artery occlusion (tMCAO). Sensorimotor outcomes were assessed by cylinder test and corner test up to 35 days and brain repair dynamics evaluated immunohistologically up to 56 days after tMCAO. Mice receiving dietary supplementation of n-3 PUFAs for 3 months showed significant increases in brain ratio of n-3/n-6 PUFA contents, and markedly reduced long-term sensorimotor deficits and chronic ischemic brain tissue loss after tMCAO. Mechanistically, n-3 PUFAs robustly promoted post-ischemic angiogenesis and neurogenesis, and enhanced white matter integrity after tMCAO. The Pearson linear regression analysis revealed that the enhancement of neurogenesis and white matter integrity both correlated positively with improved sensorimotor activities after tMCAO. This study demonstrates that prophylactic dietary supplementation of n-3 PUFAs effectively improves long-term stroke outcomes in aged mice, perhaps by promoting post-stroke brain repair processes such as angiogenesis, neurogenesis, and white matter restoration.
Highlights
Ischemic stroke is a major cause of disability in the elderly worldwide, and with prolonged life expectancies, the aged population is significantly growing to represent a significant stroke population
Our previous research using either dietary supplementation or transgenic overexpression of fat-1 to bolster systemic n-3 polyunsaturated fatty acids (PUFA) before ischemic injury in mice suggests that cerebral accumulation of n-3 PUFAs upregulated expression of angiopoietin 1 and angiopoietin 2, which contribute to enhanced angiogenesis, neurogenesis, and oligodendrogenesis after ischemic stroke [23,24,25]
To assess whether the n-3 to n-6 PUFAs ratio can be shifted by dietary supplementation in aged mice, fatty acids were analyzed in the forebrains of n-3 PUFA-supplemented (“N3 high” or N3H) and control diet-fed (“N3 low” or N3L) mice using gas chromatography beginning three months after the initiation of the diet regimen
Summary
Ischemic stroke is a major cause of disability in the elderly worldwide, and with prolonged life expectancies, the aged population is significantly growing to represent a significant stroke population. Our previous research using either dietary supplementation or transgenic overexpression of fat-1 to bolster systemic n-3 PUFAs before ischemic injury in mice suggests that cerebral accumulation of n-3 PUFAs upregulated expression of angiopoietin 1 and angiopoietin 2, which contribute to enhanced angiogenesis, neurogenesis, and oligodendrogenesis after ischemic stroke [23,24,25]. Given the context that aging itself impacts n-3 PUFAs content in the brain, and that ischemic stroke elicits more severe injury in aged animals, we hypothesized that dietary supplementation with n-3 PUFAs would greatly improve stroke outcomes in aged mice. N-3 PUFAs significantly enhanced post-stroke angiogenesis, neurogenesis, and protected white matter integrity. Prophylactic administration of n-3 PUFA-enriched fish oil in aged individuals may serve as a potential and promising therapeutic candidate for preventing neurobehavioral disorders induced by cerebral ischemia and stimulating restoration of neurovascular unit and white matter integrity in the aged brain after stroke
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