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Backgrounds and aims: Clinical studies demonstrated that the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic agent in several neurological diseases such as Parkinson disease (PD), Huntington disease (HD), and migraine. The purpose of this study is to investigate oxidative stress effects, antioxidant enzymes activity, neuroinflammatory markers levels, and neurological outcome in acute ischemic stroke (AIS) patients following administration of CoQ10 (300 mg/day). Methods: Patients with AIS ( n  = 60) were randomly assigned to a placebo group (wheat starch, n  = 30) or CoQ10-supplemented group (300 mg/day, n  = 30). The intervention was administered for 4 weeks. Serum CoQ10 concentration, malondialdehyde (MDA), superoxide dismutase (SOD) activity, glial fibrillary acidic protein (GFAP) levels as primary outcomes and National Institute of Health Stroke Scale (NIHSS), Modified Ranking Scale (MRS), and Mini-Mental State Examination (MMSE) as secondary outcome were measured at the both beginning and end of the study. Results: Forty-four subjects with AIS completed the intervention study. A significant increase in CoQ10 level was observed in the supplement-treated group compared with placebo group (mean difference = 26.05 ± 26.63 ng/ml, 14.12 ± 14.69 ng/ml, respectively; P  = 0.01), moreover CoQ10 supplementation improved NIHSS and MMSE scores significantly ( P  = 0.05, P  = 0.03 respectively). but there were no statistically significant differences in MRS score, MDA, SOD, and GFAP levels between the two groups. Conclusions: CoQ10 probably due to low dose and short duration of supplementation, no favorable effects on MDA level, SOD activity and GFAP level.

The prevalence of ischemic stroke in metabolic syndrome (MetS) is continually increasing and produces a great impact on both qualities of life and annual healthcare budget. Due to the efficiency limitation of the current therapeutic strategy, the poor availability of polyphenol substances induced by the first pass effect and the beneficial effects of mulberry fruit and ginger on brain and MetS-related diseases together with the synergistic concept, the neuroprotective effect against ischemic stroke in MetS condition of phytosome containing the combined extract of mulberry fruit and ginger (PMG) has been considered. To explore the neuroprotective effect and possible underlying mechanism of PMG on brain damage in cerebral ischemic rat with MetS, male Wistar rats were induced MetS by high-carbohydrate high-fat diet (HCHF) for 16 weeks and subjected to the cerebral ischemia/reperfusion injury (CIRI) at the right middle cerebral artery (Rt. MCAO). PMG at doses of 50, 100, and 200 mg/kg were orally fed with for 21 days, and they were assessed brain damage, neurological deficit score, and the changes of oxidative stress markers, inflammatory markers, PPAR γ expression, and epigenetic modification via DNMT-1 were performed. All doses of PMG significantly improved brain infarction, brain edema, and neurological deficit score. In addition, the reduction in DNMT-1, MDA level, NF- κ B, TNF α , and C-reactive protein together with the increase in SOD, CAT, and GPH-Px activities, and PPAR γ expression in the lesion brain were also observed. The current data clearly revealed the neuroprotective effect against cerebral ischemia with MetS condition. The possible underlying mechanism might occur partly via the suppression of DNMT-1 giving rise to the improvement of signal transduction via PPAR γ resulting in the decreasing of inflammation and oxidative stress. In conclusion, PMG is the potential neuroprotectant candidate against ischemic stroke in the MetS condition. However, the clinical trial is still essential., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Nut Palachai et al.)

Background: Cerebral stroke, with ischemic stroke being its most common type, is the leading cause of chronic disability. The ketogenic diet has been used for treating seizures for centuries and has been considered to be a treatment for other neurologic diseases in recent years. The goal of this study is to evaluate the effects of ketogenic diet preconditioning on the early motor-behavior outcome of rats with induced cerebral ischemic stroke., Methods: Twenty-four rats were surveyed in 3 groups of Main, Control, and Sham. The Main group received a ketogenic diet plus medium chain triglyceride oil starting 3 days prior to stroke induction, while the other 2 groups took a normal diet. Subsequently, Endothelin-1 was injected stereotactically near the middle cerebral artery to induce an ischemic stroke in the Main and Control group. Normal saline was injected to the members of the Sham group with the same technique. The motor-behavior functions of the rats were compared between 3 groups using adjusting step, beam, and cylinder tests., Results: After stroke induction, rats on ketogenic diet were able to adjust their steps more efficiently, moved faster on the beam, and used their hands more symmetrically in the transparent cylinder in relation to the rats in the Control group., Conclusion: It seems that ketogenic diet preconditioning improves the early motor-behavioral outcome of ischemic stroke., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: A possible target for stroke management is modulation of neuroinflammation. Evidence suggests that food components may exert anti-inflammatory properties and thus may reduce stroke-induced brain damage., Aim: To investigate the efficacy of a diet, containing anti-inflammatory ingredients, as treatment for focal ischemic brain damage induced by photothrombotic stroke in the somatosensory cortex of rats., Results: Brain lesions were surrounded by strong astrogliosis on both day 7 and day 21 after stroke and were accompanied by a trend toward globally decreased glucose metabolism on day 7. The investigational diet applied 2 weeks before the ischemia did not affect astrocyte activation on day 7, but reduced it at day 21. The investigational diet applied immediately after the ischemia, increased astrocyte activation on day 7 and completely reversed this effect on day 21. Moreover, postischemic intervention increased glucose metabolism in somatosensory cortex ipsilateral to the lesion on day 7., Conclusion: This study reveals potentially beneficial effects of a diet containing elevated amounts of anti-inflammatory nutrients on the recovery from ischemic brain damage. Therefore, dietary intervention can be considered as an adjuvant therapy for recovery from this brain pathology., (© 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

BACKGROUND Ischemic stroke, featuring high incidence, morbidity, and mortality, is one of the three major diseases troubling human beings. The purpose of the study was to examine the impact of early high-protein diet on neurofunctional recovery in rats with ischemic stroke as well as their cerebral infarct areas and molecular expressions of oxidative stress. MATERIAL AND METHODS The middle cerebral artery occlusion model (MCAO) was established, and 48 adult, male Sprague Dawley (SD) rats of clean grade aged seven to eight months (250-280 g body weight) were randomized into four groups: the MCAO group with high-protein diet (MH), the MCAO group with standard-protein diet (MS), the sham group with high-protein diet (SH), and the sham group with standard-protein diet (SS). High-protein diet intervention started on the first day of the surgery, and the rats' body weights and their neurological deficit scores were measured on each postoperative day while the scores of motors coordination and balance ability were recorded every other day. In addition, their cerebral infant areas and the molecular expressions of oxidative stress injuries were detected as well. RESULTS Compared to the MS group, the rats in the MH group gained faster weight growth (p<0.05), presented significantly lower neurological impairment scores (p<0.05), remarkably improved motor coordination and balance ability (p<0.05) as well as showed smaller cerebral infarct areas (p<0.05), increased expression of SOD (superoxide dismutase), and reduced expressions of MDA (malondialdehyde) and iNOS (inducible nitric oxide synthase). However, there was no significant difference between the SS group and the SH group (p>0.05). CONCLUSIONS Early high-protein diet facilitates the recovery of body weights and neurological functions as well the reduction of the cerebral infarct areas of rats, thus alleviating ischemic stroke-caused oxidative stress injuries.

Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla magnetic resonance imaging (MRI) scanner to assess brain perfusion, integrity, and functional connectivity. To assess brain plasticity, inflammation, and vascular integrity, immunohistochemistry was performed after killing of the mice. We found that the multinutrient intervention had diverse effects on the stroke-induced impairments in females. Similar to previous observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the female stroke mice seem more modest in comparison to previously investigated male stroke mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender-specific) treatment regimens for cerebrovascular diseases such as stroke. This article is part of the Special Issue "Vascular Dementia"., (© 2017 International Society for Neurochemistry.)

Reperfusion therapy is one of the main treatment strategies of ischemic stroke. The first studies of the efficacy of thrombolytic medications started form the use of streptokinase and fibrinolysin in patients with ischemic stroke in late 50 - early 60 of the XX century in the United States, Soviet Union, and Western Europe. After the development of recombinant tissue plasminogen activator, thrombolysis became one of the main methods of reperfusion in patients with acute ischemic stroke, acute myocardial infarction, or other acute vascular thrombotic events. Later, modified variants of tissue plasminogen activator with prolonged clearance time, high fibrin-selectivity, and bolus delivery were introduced. Another group of thrombolytic agents includes derivatives of flora and fauna - external plasminogen activators, of which streptokinase, staphylokinase, and desmoteplase are most common drugs. These medications are not a structural part of the human organism, and overcoming of immunogenicity while preserving fibrinolytic activity and fibrin specificity is one of the main tasks in applying them in clinical practice.

Memory and cognition impairments resultant of ischemic stroke could be minimized or avoided by antioxidant supplementation. In this regard, the neuroprotective potential of Green tea from Camellia sinensis has been investigated. However, there is a lack of information regarding the neuroprotective potential of others teas processed from the Camellia sinensis. Here we investigate the neuroprotective role of green, red, white and black tea on memory deficits and brain oxidative stress in a model of ischemic stroke in rats. Our findings show that green and red teas prevent deficits in object and social recognition memories, but only green tea protects against deficits in spatial memory and avoids hippocampal oxidative status and intense necrosis and others alterations in the brain tissue. In summary, green tea shows better neuroprotection in ischemic stroke than the others teas from Camellia sinensis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Aims: Vitamin D deficiency is a common problem in stroke survivors. Observational studies have reported an association of low vitamin D levels with greater stroke severity, poststroke mortality and functional disability. Randomised clinical trials are lacking. We sought to assess the effect of calcium and vitamin D supplementation in ischaemic stroke survivors with vitamin D deficiency/insufficiency on disability/mortality outcomes., Methods: In this randomised controlled open-label trial, 73 patients of acute ischaemic stroke were screened for serum 25 hydroxy Vitamin D (25(OH)D) levels. A total of 53 patients with baseline 25(OH)D <75 nmol/L were randomised into two arms. One received vitamin D and calcium supplementation along with usual care (n=25) and the other received usual care alone (n=28). Primary outcome was the proportion of patients achieving a good outcome [modified Rankin Scale score 0-2] at 6 months and all cause mortality at 6 months., Results: The age (mean±SD) of participants was 60.4±11.3 years, 69.8% were males. The proportion of patients achieving good outcome was higher in the intervention arm (Adjusted OR 1.9, 95% CI 0.6-6.4; P=.31). The survival probability was greater in the intervention arm (83.8%, CI 62.4-93.6) as compared with the control arm (59.5%, CI 38.8-75.2; P=.049) with adjusted Hazard ratio (HR) of 0.26 (95% CI 0.08-0.9; P=.03)., Conclusions: This is the first randomised controlled study assessing the effect of vitamin D and calcium supplementation on ischaemic stroke outcomes and points towards a potential benefit. Findings need to be validated by a larger trial., (© 2016 John Wiley & Sons Ltd.)

Stroke is a leading cause of disability and death worldwide. Numerous therapeutics applied acutely after stroke have failed to improve long-term clinical outcomes. An emerging direction is nutritional intervention with omega-3 polyunsaturated fatty acids acting as disease-modifying factors and targeting post-stroke disabilities. Our previous studies demonstrated that the omega-3 precursor, alpha-linolenic acid (ALA) administrated by injections or dietary supplementation reduces stroke damage by direct neuroprotection, and triggering brain artery vasodilatation and neuroplasticity. Successful translation of putative therapies will depend on demonstration of robust efficacy on common deficits resulting from stroke like loss of motor control and memory/learning. This study evaluated the value of ALA as adjunctive therapy for stroke recovery by comparing whether oral or intravenous supplementation of ALA best support recovery from ischemia. Motor and cognitive deficits were assessed using rotarod, pole and Morris water maze tests. ALA supplementation in diet was better than intravenous treatment in improving motor coordination, but this improvement was not due to a neuroprotective effect since infarct size was not reduced. Both types of ALA supplementation improved spatial learning and memory after stroke. This cognitive improvement correlated with higher survival of hippocampal neurons. These results support clinical investigation establishing therapeutic plans using ALA supplementation., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: High adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower risk of hypertension, the major risk factor for stroke. We examined whether adherence to the DASH diet is inversely associated with the incidence of stroke., Methods: The study population comprised 74 404 men and women (45-83 years of age), without stroke at baseline, from the Cohort of Swedish Men and the Swedish Mammography Cohort. Diet was assessed with a food-frequency questionnaire. A modified DASH diet score was created based on consumption of vegetables, fruits, legumes and nuts, whole grains, low-fat dairy, red meat and processed meat, and sweetened beverages. Stroke cases were identified through linkage to the Swedish National Patient and Cause of Death Registers. Relative risks and 95% confidence intervals were estimated using Cox proportional hazards regression model., Results: During 882 727 person-years (mean, 11.9 years) of follow-up, 3896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages were ascertained. The modified DASH diet score was statistically significantly inversely associated with the risk of ischemic stroke (P for trend=0.002), with a multivariable relative risk of 0.86 (95% confidence interval, 0.78-0.94) for the highest versus the lowest quartile of the score. The modified DASH diet score was nonsignificantly inversely associated with intracerebral hemorrhage (corresponding relative risk=0.81; 95% confidence interval, 0.63-1.05) but was not associated with subarachnoid hemorrhage., Conclusions: These findings indicate that high adherence to the DASH diet is associated with a reduced risk of ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01127698 and NCT01127711 for the Swedish Mammography Cohort and the Cohort of Swedish Men, respectively., (© 2016 American Heart Association, Inc.)

Objective: to study the efficacy of cytoflavin in thrombolytic treatment of patients with acute ischemic stroke (IS)., Material and Methods: Fifty-five patients in the acute stage of IS were examined. The National Institutes of Health Stroke scale (NIHSS), the Rankin scale and the Barthel index of activities of daily living were used. Depending on the scheme of treatment, patients were divided into 2 groups: the first (basic) group included 29 patients who received cytoflavin immediately after thrombolytic therapy. The control group (26 patients) received basic vascular and neuroprotective treatment., Results and Conclusion: The marked reduction in the severity of neurological symptoms to the 10th day of treatment and higher probability of a successful outcome were noted in the basic group compared to the controls. There was an improvement of functional activities according to the Rankin scale and of activities of daily living assessed by the Barthel index, with scores "moderate dependence" in the basic group and "severe dependence" in the control group. The inclusion of cytoflavin in the treatment scheme of patients with acute IS increased the efficacy of treatment.

Background: The effects of green tea intake on risk of cardiovascular disease (CVD) have not been well-defined. The aim of this meta-analysis was to evaluate the association between green tea consumption, CVD, and ischemic related diseases., Methods: All observational studies and randomized trials that were published through October 2014 and that examined the association between green tea consumption and risk of cardiovascular and ischemic related diseases as the primary outcome were included in this meta-analysis. The quality of the included studies was evaluated according to the Cochrane Handbook 5.0.2 quality evaluation criteria., Results: A total of 9 studies including 259,267 individuals were included in the meta-analysis. The results showed that those who didn't consume green tea had higher risks of CVD (OR=1.19, 95% CI: 1.09-1.29), intracerebral hemorrhage (OR=1.24, 95% CI: 1.03-1.49), and cerebral infarction (OR=1.15, 95% CI: 1.01-1.30) compared to <1 cup green tea per day. Those who drank 1-3 cups of green tea per day had a reduced risk of myocardial infarction (OR=0.81, 95% CI: 0.67-0.98) and stroke (OR=0.64, 95% CI: 0.47-0.86) compared to those who drank <1 cup/day. Similarly, those who drank ≥4 cups/day had a reduced risk of myocardial infarction compared to those who drank <1 cup/day (OR=0.68, 95% CI: 0.56-0.84). Those who consumed ≥10 cups/day of green tea were also shown to have lower LDL compared to the <3 cups/day group (MD=-0.90, 95% CI: -0.95 to -0.85)., Conclusions: Our meta-analysis provides evidence that consumption of green tea is associated with favorable outcomes with respect to risk of cardiovascular and ischemic related diseases., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Brain stroke is the third most important cause of death in developed countries. We studied the effect of different dietary lipids on the outcome of a permanent ischemic stroke rat model., Methods: Wistar rats were fed diets containing 7% commercial oils (S, soybean; O, olive; C, coconut; G, grape seed) for 35 d. Stroke was induced by permanent middle cerebral artery occlusion. Coronal slices from ischemic brains and sham-operated animals were supravitally stained. Penumbra and core volumes were calculated by image digitalization after 24, 48, and 72 h poststroke. Homogenates and mitochondrial fractions were prepared from different zones and analyzed by redox status, inflammatory markers, ceramide, and arachidonate content, phospholipase A2, NOS, and proteases., Results: Soybean (S) and G diets were mainly prooxidative and proinflammatory by increasing the liberation of arachidonate and its transformation into prostaglandins. O was protective in terms of redox homeostatic balance, minor increases in lipid and protein damage, conservation of reduced glutathione, protective activation of NOS in penumbra, and net ratio of anti-to proinflammatory cytokines. Apoptosis (caspase-3, milli- and microcalpains) was less activated by O than by any other diet., Conclusion: Dietary lipids modulate NOS and PLA2 activities, ceramide production, and glutathione import into the mitochondrial matrix, finally determining the activation of the two main protease systems involved in programmed cell death. Olive oil appears to be a biological source for the isolation of protective agents that block the expansion of brain core at the expense of penumbral neurons., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Triheptanoin, an oily substance, consists of glycerol bound to three molecules of heptanoic acid, a C7 odd-chain fatty acid. A triheptanoin-rich diet has anaplerotic effects because heptanoate metabolism yields succinate which delivers substrates to the Krebs cycle. While previous studies on the effects of triheptanoin focused on metabolic disorders and epilepsy, we investigated triheptanoin's effect on ischemic stroke. Mice were fed a triheptanoin-enriched diet for 14days; controls received soybean oil. Only mice fed triheptanoin had measurable quantities of odd-numbered fatty acids in the plasma and brain. Transient ischemia was induced in the brain by occlusion of the middle cerebral artery (MCAO) for 60min. One day later, mice were tested for neurological function (chimney, rotarod and corner tests) which was found to be better preserved in the triheptanoin group. Microdialysis demonstrated that the strong, neurotoxic increase of extracellular glutamate, which was observed in the mouse striatum during MCAO, was strongly reduced in triheptanoin-fed mice while glucose levels were not affected. Triheptanoin diet reduced the infarct area in stroked mice by about 40%. In ex vivo-experiments with isolated mitochondria, ischemia was found to cause a reduction of mitochondrial respiratory activity. This reduction was attenuated by triheptanoin diet in complex II and IV. In parallel measurements, ATP levels and mitochondrial membrane potential were reduced in control animals but were preserved in triheptanoin-fed mice. We conclude that triheptanoin-fed mice which sustained an experimental stroke had a significantly improved neurological outcome. This beneficial effect is apparently due to an improvement of mitochondrial function and preservation of the cellular energy state. Our findings identify triheptanoin as a promising new dietary agent for neuroprotection., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Caloric restriction (CR) has been shown to have several health benefits and provides protection against type 2 diabetes, neurodegenerative and cerebral vascular diseases. It reduces the brain infarct size and promotes neurological functional recovery after cerebral ischemia. Sirtuin 1 (SIRT1) plays an important role in the biological effects induced by CR. This study investigated the role of SIRT1 in ischemic tolerance in the brain induced by CR. Sprague drawly rats were divided into two groups based on food intake. Ad libitum (AL) group was fed with normal diet while the CR group received 60% calories compared to AL. All animals were subjected to a middle cerebral artery occlusion for 90 min. Results showed the neurological function score of CR group was higher and the brain infarct volume was markedly reduced in CR group compared to AL group at 24h after reperfusion (p < 0.05). CR increased the synthesis of SIRT1 significantly (p < 0.05), and ameliorated the down regulation of SIRT1 expression at 6 and 12h after middle cerebral artery occlusion (p < 0.05, p < 0 .01, respectively). Knockdown of SIRT1 by siRNA in vivo reversed the neuroprotective effect of CR. From this study, we deduce that CR induces brain ischemic tolerance on rats via increasing the synthesis of SIRT1., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To evaluate an impact of low calorie diet therapy (LCDT) on cerebral hemodynamics, cognitive functions and quality-of-life of patients with arterial hypertension and chronic cerebral ischemia., Material and Methods: The main group consisted of 22 patients, 16 women and 6 men (mean age 54.4±2.4 years), assigned to the diet. The comparison group included 20 patients, 12 women and 8 men (mean age 55.6±1,0 years), who received standard antihypertensive treatment. The results of Doppler ultrasound of cerebral arteries, cognitive functions and quality-of-life were assessed after 6 months of treatment., Results and Conclusion: A positive effect of LCDT on the cerebral hemodynamics, cognitive functions and quality-of-life indices maintained for 6 months. The efficacy of LCDT was comparable to that of standard treatment in the comparison group.

We evaluated the neuroprotective effects of an anti-oxidative nutrient rich enteral diet (AO diet) that contained rich polyphenols (catechins and proanthocyanidins) and many other anti-oxidative ingredients. Wistar rats were treated with either vehicle, normal AO diet (containing 100kcal/100mL, catechin 38.75mg/100mL and proanthocyanidin 19mg/100mL, 1mL/day), or high AO diet (containing 10 times the polyphenols of the normal AO diet) for 14 days, and were subjected to 90min of transient middle cerebral artery occlusion. The AO diet improved motor function, reduced cerebral infarction volume, and decreased both peroxidative markers such as 4-hydroxynonenal, advanced glycation end products, 8-hydroxy-2-deoxyguanosine and inflammatory markers such as monocyte chemotactic protein-1, ionized calcium-binding adapter molecule-1, and tumor necrosis factor-α. Our study has shown that an AO diet has neuroprotective effects through both anti-oxidative and anti-inflammatory mechanisms, indicating that nutritional control with polyphenols could be useful for patients with acute ischemic stroke., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sutherlandia (Sutherlandia frutescens) and elderberry (Sambucus spp.) are used to promote health and for treatment of a number of ailments. Although studies with cultured cells have demonstrated antioxidative and anti-inflammatory properties of these botanicals, little is known about their ability to mitigate brain injury. In this study, C57BL/6 J male mice were fed AIN93G diets without or with Sutherlandia or American elderberry for 2 months prior to a 30-min global cerebral ischemia induced by occlusion of the bilateral common carotid arteries (BCCAs), followed by reperfusion for 3 days. Accelerating rotarod assessment at 24 h after BCCA occlusion showed amelioration of sensorimotor impairment in the mice fed the supplemented diets as compared with the ischemic mice fed the control diet. Quantitative digital pathology assessment of brain slides stained with cresyl violet at 3 days after ischemia/reperfusion (I/R) revealed significant reduction in neuronal cell death in both dietary groups. Immunohistochemical staining for ionized calcium-binding adapter molecule-1 demonstrated pronounced activation of microglia in the hippocampus and striatum in the ischemic brains 3 days after I/R, and microglial activation was significantly reduced in animals fed supplemented diets. Mitigation of microglial activation by the supplements was further supported by the decrease in expression of p47phox, a cytosolic subunit of NADPH oxidase, and phospho-ERK1/2, a mitogen-activated protein kinase known to mediate a number of cytoplasmic processes including oxidative stress and neuroinflammatory responses. These results demonstrate neuroprotective effect of Sutherlandia and American elderberry botanicals against oxidative and inflammatory responses to cerebral I/R., (© The Author(s) 2014.)

Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, energy failure, free radical production, excitotoxicity, altered calcium homeostasis, and activation of proteases all of which affect brain functioning and also contribute to longterm disabilities including cognitive decline. Inflammation, mitochondrial dysfunction, increased oxidative/nitrosative stress, and intracellular calcium overload contribute to brain injury including cell death and brain edema. However, there is a paucity of agents that can effectively reduce cerebral damage and hence considerable attention has focused on developing newer agents with more efficacy and fewer side-effects. Polyphenols are natural compounds with variable phenolic structures and are rich in vegetables, fruits, grains, bark, roots, tea, and wine. Most polyphenols have antioxidant, anti-inflammatory, and anti-apoptotic properties and their protective effects on mitochondrial functioning, glutamate uptake, and regulating intracellular calcium levels in ischemic injury in vitro have been demonstrated. This review will assess the current status of the potential effects of polyphenols in reducing cerebral injury and improving cognitive function in ischemia in animal and human studies. In addition, the review will also examine available patents in nutrition and agriculture that relates to cerebral ischemic injury with an emphasis on plant polyphenols.

Objectives: To investigate the effects of garlic on endothelial function in patients with ischemic stroke (ISS)., Design: Cross-sectional study., Participants: 125 Chinese patients with prior ISS due to athero-thrombotic disease were recruited from the outpatient clinics during July 2005 to December 2006., Measurements: Daily allium vegetable intake (including garlic, onions, Chinese chives and shallots) was ascertained by means of a validated food frequency questionnaire for Chinese and brachial artery flow-mediated dilatation (FMD) was measured using high-resolution ultrasound in all subjects., Results: The mean age of the study population was 65.9±11.1 years and 69% were males. Mean allium vegetable intake and garlic intake of the study population was 7.5±12.7g/day and 2.9±8.8g/day respectively. Their mean FMD was 2.6±2.3%. Daily intake of total allium vegetable (r=0.36, P<0.01) and garlic (r=0.34, P<0.01) significantly correlated with FMD. Using the median daily allium intake as cut-off (3.37g/day), patients with a low allium intake <3.37g/day was noted to have a lower FMD compared to those with a normal allium intake (2.1±2.1% versus 3.0±2.4%, P<0.05). After adjusting for confounding factors, multi-variate analysis identified that daily allium vegetable (B=0.05, 95% confidence interval: 0.02, 0.09, P<0.01) and garlic (B=0.07, 95% confidence interval: 0.02, 0.12, P<0.01) intake, but not onions, Chinese chives and shallots were independent predictors for changes in FMD in patients with ISS., Conclusions: Daily garlic intake is an independent predictor of endothelial function in patients with ISS and may play a role in the secondary prevention of atherosclerotic events.

Background and Purpose: Neurovascular damage, including neuronal apoptosis and blood-brain barrier (BBB) damage, and microglia activation account for the hypoxic-ischemia (HI) susceptibility in neonatal brain. The p53 upregulation is involved in apoptosis, endothelial cell damage, and microglia activation. We hypothesized that underweight induced by dietary restriction (DR) protects against HI in rat pups by attenuating p53-mediated neurovascular damage., Methods: Male rat pups were grouped as normal litter (NL) size (12 pups/dam), DR (18 pups/dam), and extreme DR (24 pups/dam) from postnatal day 1 and subjected to HI on postnatal day 7. Immunohistochemistry and immunoblotting were used to determine p53, phospho-murine double minute-2, caspases, BBB damage and microglia activation, and immunofluorescence to determine the cellular distribution of p53. Pharmacological approaches were used to regulate p53., Results: The NL, DR, and extreme DR pups had similar TUNEL-positive cells and caspases on postnatal day 7 and comparable learning performance at adulthood. After HI, the DR-HI, but not extreme DR-HI, pups had significantly lower p53, higher phospho-murine double minute-2, lower cleaved caspases, less BBB damage and microglia activation, and less brain volume loss than NL-HI pups. In NL-HI pups, p53 expression was located mainly in the neurons, endothelial cells, and microglia. The p53 blockage by pifithrin-α in NL-HI pups decreased apoptosis, BBB damage, and microglia activation, and was neuroprotective. In contrast, upregulating p53 by nutlin-3 in DR-HI pups increased apoptosis, BBB damage, and microglia activation, and worsened brain damage., Conclusions: Moderate DR, but not extreme DR, reduces p53-mediated neurovascular damage after HI and confers long-term protection in neonatal brain.

Stroke remains the number one cause of disability in the adult population. Despite scientific progress in our understanding of stroke pathology, only one treatment (tissue plasminogen activator or tPA) is able to afford benefits but to less than 3% of ischemic stroke patients. The development of experimental dietary supplement therapeutics designed to stimulate endogenous mechanisms that confer neuroprotection is likely to open new avenues for exploring stroke therapies. The present review article evaluates the recent literature supporting the benefits of dietary supplementation for the therapy of ischemic stroke. This article focuses on discussing the medical benefits of NT-020 as an adjunct agent for stroke therapy. Based on our preliminary data, a pre-stroke treatment with dietary supplementation promotes neuroprotection by decreasing inflammation and enhancing neurogenesis. However, we recognize that a pre-stroke treatment holds weak clinical relevance. Thus, the main goal of this article is to provide information about recent data that support the assumption of natural compounds as neuroprotective and to evaluate the therapeutic effects of a dietary supplement called NT-020 as in a stroke model. We focus on a systematic assessment of practical treatment parameters so that NT-020 and other dietary supplementations can be developed as an adjunct agent for the prevention or treatment of chronic diseases. We offer rationale for determining the optimal dosage, therapeutic window, and mechanism of action of NT-020 as a dietary supplement to produce neuroprotection when administered immediately after stroke onset. We highlight our long-standing principle in championing both translational and basic science approaches in an effort to fully reveal the therapeutic potential of NT-020 as dietary supplementation in the treatment of stroke. We envision dietary supplementation as an adjunct therapy for stroke at acute, subacute, and even chronic periods.

Background and Aims: Stroke is the number one cause of death in China. Although the effective management has reduced the mortality and lengthened survival, little attention has been paid to nutritional issues in patients with stroke in China. This study aimed to assess the premorbid nutrition status in dying patients with acute cerebral infarction., Methods: In this study, a total of 185 acute ischemic stroke patients dying within 30 days were recruited from medical records. Characteristics of dying patients were assessed on admission, and serum biochemical parameters including serum total protein, serum albumin, and serum prealbumin were measured within 24 hours after stroke onset and every week routinely., Results: Among 185 ischemic stroke patients, 86 dying patients experienced their first-ever acute cerebral infarction, while 99 dying patients were experiencing a recurrent cerebral infarction. The prevalence of dysphagia, post-stroke pneumonia, and gastrointestinal hemorrhage in recurrent stroke groups were higher than those in the first-ever stroke group (P<0.01). There were gradually declines in serum total protein, serum albumin, and serum prealbumin in dying patients from admission to death, especially in the recurrent ischemic stroke group, as compared to their normal range. The sensitive sequence of serum nutritional index for dying patients with ischemic infarction was: serum prealbumin>serum albumin>serum total protein., Conclusions: This study showed that hypoproteinemia and undernutrition were serious in dying patients with acute ischemic stroke, especially in patients with recurrent ischemic stroke. This study also confirmed that serum prealbumin is more sensitive than serum albumin to assess nutritional status. The strategies to improve malnutrition in stroke patients are urgently needed in China.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a group of essential fatty acids that serve as energy substrates and integral membrane components, and therefore play crucial roles in the maintenance of normal neurological function. Recent studies show that n-3 PUFAs display neuroprotective properties and exert beneficial effects on the cognitive function with aging. The brain's need of n-3 PUFAs is predominantly met by the blood delivery due to their limited synthesis in the brain. The present review focuses on the metabolism of n-3 PUFAs in the brain, including their accumulation and turnover. We also highlight the current understanding of the neuroprotective effects of n-3 PUFAs against cerebral ischemia and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

In patients who undergo rehabilitation after ischemic stroke, nutrition strategies are adopted to provide tube-fed individuals with adequate nutrition and/or to avoid the body wasting responsible for poor functional outcome and prolonged stay in the hospital. Investigations have documented that nutrition interventions can enhance the recovery of neurocognitive function in individuals with ischemic stroke. Experimental studies have shown that protein synthesis is suppressed in the ischemic penumbra. In clinical studies on rehabilitation patients designed to study the effects of counteracting or limiting this reduction of protein synthesis by providing protein supplementation, patients receiving such supplementation had enhanced recovery of neurocognitive function. Cellular damage in cerebral ischemia is also partly caused by oxidative damage secondary to free radical formation and lipid peroxidation. Increased oxidative stress negatively affects a patient's life and functional prognosis. Some studies have documented that nutrition supplementation with B-group vitamins may mitigate oxidative damage after acute ischemic stroke. Experimental investigations have also shown that cerebral ischemia changes synaptic zinc release and that acute ischemia increases zinc release, aggravating neuronal injury. In clinical practice, patients with ischemic stroke were found to have a lower than recommended dietary intake of zinc. Patients in whom daily zinc intake was normalized had better recovery of neurological deficits than subjects given a placebo. The aim of this review is to highlight those brain metabolic alterations susceptible to nutrition correction in clinical practice. The mechanisms underlying the relationship between cerebral ischemia and nutrition metabolic conditions are discussed.

The ability of a soy-based high-phytoestrogen diet (nutritional intervention) or genistein (pharmacological intervention), to limit ischemic brain damage in Wistar, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, has been assessed. As to the nutritional intervention, two groups from each strain received either a phytoestrogen-free (PE-0) or a high-phytoestrogen (PE-600) diet from weaning to adulthood. As to the pharmacological intervention, all animals were fed the standard soy-free AIN-93G diet and subsequently separated into two groups from each strain to receive either pure genistein (aglycone form, 1mg/kg/day intraperitoneal) or vehicle at 30 min reperfusion. After an episode of 90 min ischemia (intraluminal thread procedure) followed by 3 days reperfusion, cerebral infarct volume was measured. Arterial blood pressure (ABP) was significantly higher at the basal stage (just before ischemia) in SHR (140 ± 7 mmHg, n=17, p<0.05) than in Wistar (113 ± 4mmHg, n=23) and WKY (111 ± 6mmHg, n=14) rats. No significant differences were shown among the three stages (basal, ischemia, reperfusion) within each rat strain for both PE-0 and PE-600 diets. Wistar, but not WKY or SHR, rats fed the PE-600 diet showed significantly lower infarct volumes than their counterparts fed the PE-0 diet (30 ± 3% vs. 17 ± 3%, p<0.01). Genistein-treated Wistar, but not WKY or SHR, rats showed significantly lower infarct volumes than their vehicle-treated controls (27 ± 2% vs. 15 ± 2%, p<0.01). Our results demonstrate that: (1) the neuroprotective action of either chronic or acute exposure to soy isoflavones is strain-dependent, since it was shown in Wistar but not WKY or SHR rats; and (2) the soy-based diet does not prevent development of hypertension in SHR rats., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Polyphenols are natural substances with variable phenolic structures and are enriched in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. Recent interest in polyphenols has increased greatly due to their potential antioxidant effects. In addition, some polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties although some of these properties may be a consequence of their anti-oxidant effects. Given that oxidative stress and inflammation are hypothesized to contribute to increased neural damage in ischemia, polyphenols appear to have a tremendous potential in attenuating such injuries. One important consequence of ischemia is brain edema and oxidative stress and inflammation are implicated in its pathogenesis. Brain edema is defined as an abnormal accumulation of fluid in the brain parenchyma resulting in a volumetric enlargement of the cells or tissue and can cause further ischemic damage. The purpose of this article is to review the current literature on brain edema and/or cell swelling in ischemic injury with the goal to identify newer approaches to attenuate brain edema. A review of currently known mechanisms underlying edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce edema will be critically reviewed with the discussion of some recent patents.

Background and Purpose: Fish-derived omega-3 fatty acids have long been associated with cardiovascular protection. In this trial, we assessed whether treatment with a guideline-recommended moderate-dose fish oil supplement could improve cardiovascular biomarkers, mood- and health-related quality of life in patients with ischemic stroke., Methods: Patients with CT-confirmed stroke were randomized to 3 g/day encapsulated fish oil containing approximately 1.2 g total omega-3 (0.7 g docosahexaenoic acid; 0.3 g eicosapentaenoic acid) or placebo oil (combination palm and soy) taken daily over 12 weeks. Serum triglycerides, total cholesterol and associated lipoproteins, selected inflammatory and hemostatic markers, mood, and health-related quality of life were assessed at baseline and follow-up. The primary outcome was change in triglycerides. Compliance was assessed by capsule count and serum phospholipid omega-3 levels (Australian Clinical Trials Registration: ACTRN12605000207617)., Results: One hundred two patients were randomized to fish oil or placebo. Intention-to-treat and per-protocol (>85% compliance) analyses showed no significant effect of fish oil treatment on any lipid, inflammatory, hemostatic, or composite mood parameters measured. Adherence to treatment based on pill count was good (89%) reflected by increased serum docosahexanoic acid (P<0.001) and eicosapentaenoic acid (P=0.0006) in the fish oil group. Analysis of oil composition, however, showed some degradation and potentially adverse oxidation products at the end of the study., Conclusions: There was no effect of 12 weeks of treatment with moderate-dose fish oil supplements on cardiovascular biomarkers or mood in patients with ischemic stroke. It is possible that insufficient dose, short duration of treatment, and/or oxidation of the fish oils may have influenced these outcomes.

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1alpha, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1alpha) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1alpha. The neuroprotective effect of diet-induced ketosis (3 weeks of feeding a ketogenic diet), as pretreatment, on infarct volume, after reversible middle cerebral artery occlusion (MCAO), and the upregulation of HIF-1alpha were investigated. The effect of beta-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1alpha and Bcl-2 (anti-apoptotic protein) proteins and succinate content were measured. A 55% or 70% reduction in infarct volume was observed with BHB infusion or diet-induced ketosis, respectively. The levels of HIF-1alpha and Bcl-2 proteins increased threefold with diet-induced ketosis; BHB infusions also resulted in increases in these proteins. As hypothesized, succinate content increased by 55% with diet-induced ketosis and fourfold with BHB infusion. In conclusion, the biochemical link between ketosis and the stabilization of HIF-1alpha is through the elevation of succinate, and both HIF-1alpha stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Free radicals are involved in neurodegenerative disorders, such as ischemia and aging. We have previously demonstrated that treatment with diets enriched with blueberry, spinach, or spirulina have been shown to reduce neurodegenerative changes in aged animals. The purpose of this study was to determine if these diets have neuroprotective effects in focal ischemic brain. Adult male Sprague-Dawley rats were fed with equal amounts of diets (blueberry, spinach, and spirulina) or with control diet. After 4 weeks of feeding, all animals were anesthetized with chloral hydrate. The right middle cerebral artery was ligated with a 10-O suture for 60 min. The ligature was later removed to allow reperfusional injury. Animals were sacrificed and brains were removed for caspase-3 enzymatic assays and triphenyltetrazolium chloride staining at 8 and 48 h after the onset of reperfusion. A subgroup of animals was used for locomotor behavior and biochemical assays. We found that animals which received blueberry, spinach, or spirulina enriched diets had a significant reduction in the volume of infarction in the cerebral cortex and an increase in post-stroke locomotor activity. There was no difference in blood biochemistry, blood CO2, and electrolyte levels among all groups, suggesting that the protection was not indirectly mediated through the changes in physiological functions. Animals treated with blueberry, spinach, or spirulina had significantly lower caspase-3 activity in the ischemic hemisphere. In conclusion, our data suggest that chronic treatment with blueberry, spinach, or spirulina reduces ischemia/reperfusion-induced apoptosis and cerebral infarction.

This study investigated the neuroprotective effects of dietary supplementation of fish oil on both brain infarction and the activities of antioxidant enzymes. Male Sprague-Dawley rats (4-weeks old) were divided into two groups and received either a regular diet (RD) or a fish-oil-supplemented diet (FOD) for 6 weeks prior to middle cerebral artery (MCA) occlusion. The infarction volume of the brain was calculated using image analysis after staining. Antioxidant enzymes were measured before ischemia (BI), after 2 h of ischemia (AI) and after 24 h (24hR), 48 h (48hR) and after 7 days (7dR) of reperfusion. The infarction volume of the brain was significantly smaller in the FOD group than in the RD group after 24 h of reperfusion (p<0.05). Before ischemia, the levels of lipid peroxide and the glutathione peroxidase (GPx) activity were higher in the FOD group than in the RD group. During reperfusion, the catalase (CAT) activity in the FOD group remained at the preischemia level until after 48 h of reperfusion, while those in the RD group did not. The Mn-superoxide dismutase (SOD) activity and GPx activity were higher in the FOD group than in the RD group only after 2 h of ischemia. In the fatty acid analysis, the ratio of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were higher in the FOD group than in the RD group (p<0.05). Our results demonstrate that supplementing the diet with fish oil could decrease the cerebral infarction volume following ischemia and reperfusion (I/R) partly by working directly as an antioxidant and partly by modulating antioxidant enzyme activities.

Rats fed with low (0.015%), normal (0.08%) or high (0.32%) magnesium (Mg) diet for 5-6 weeks were subjected to photothrombosis-induced infarction. As compared to normal diet, Mg deprivation increased by 45% infarct volume at 24 h after photothrombosis but did not modify the lesion at 4 h after photothrombosis. Mg supplementation did not protect from infarction whatever the time point examined. No differences in pre-ischemic systolic blood pressure and glycemia as well as in post-ischemic kaliemia, calcemia and plasma antioxidant activity were observed between groups. However, plasma total Mg level correlated with plasma antioxidant activity at 4 h after photothrombosis. These results demonstrate that brains from Mg deficient rats are more susceptible to permanent focal ischemia than rats fed with normal or high Mg diet.

Western diets consist to a large part of n-6 polyunsaturated fatty acids (PUFAs). These n-6 PUFAs and their conversion products favor immune and inflammatory reactions and compromise vasoregulation, which can contribute to the development of dementia. Recent epidemiological studies associated dementia, particularly the type accompanied by a vascular component, with high, saturated dietary fat intake. Conversely, high fish consumption (a source of long chain n-3 PUFAs) was related to a reduced risk for cognitive decline. Therefore we studied the effects of long chain n-3 PUFAs in rats with bilateral occlusion of the common carotid arteries (2VO), which mimics cerebral hypoperfusion, a risk factor for dementia. Male Wistar rats received experimental diets with a decreased (n-6)/(n-3) ratio from weaning on. At the age of 3 months, the animals underwent 2VO surgery. The rats were tested in the elevated plus maze, an active avoidance paradigm and the Morris water maze (at different survival times). Following behavioral testing, the animals were sacrificed at the age of 7 months. The frontoparietal cortex was analyzed for capillary ultrastructure with electron microscopy. No effects of cerebral hypoperfusion or diet were found on elevated plus maze and active avoidance, while spatial memory in the Morris maze was compromised due to cerebral hypoperfusion under placebo dietary conditions. n-3 PUFA supplementation in combination with extra additives improved the performance of the 2VO animals. The number of endothelial mitochondria, as well as the ratio of microvessels with degenerative pericytes appeared to be lower due to long chain n-3 PUFAs. These results may indicate an improved condition of the blood-brain barrier.

Seven late-treated patients between the ages of 10-30 years suffering from homocystinuria were examined clinically and electrophysiologically; four had MRI. The clinical examination showed extrapyramidal features and slight impairment of proprioception. Electrophysiological evaluation revealed normal results in the acoustic and central motor system; a minor, possibly vitamin B6 related, sensory neuropathy was detected by peripheral conduction studies. MR imaging showed small focal areas of gliosis in the white matter, generalized cortical atrophy in two patients, but only one small cortical infarct. No changes in the basal ganglia were detected. These results support the view that neurological signs and symptoms in patients suffering from homocystinuria are related to morphological findings, as well as pharmacological effects.