Tyrosol, a simple phenol from EVOO, targets multiple pathogenic mechanisms of neurodegeneration in a C. elegans model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder involving α-synuclein (α-syn) aggregation, oxidative stress, dysregulation of redox metal homeostasis, and neurotoxicity. Different phenolic compounds with known antioxidant or antichelating properties have been shown to also interfere with aggregation of amyloid proteins and modulate intracellular signaling pathways. The present study aims to investigate for the first time the effect of tyrosol (TYR), a simple phenol present in extra-virgin olive oil, on α-syn aggregation in a Caenorhabditis elegans model of PD and evaluate its potential to prevent α-syn toxicity, neurodegeneration, and oxidative stress in this model organism. Our results show that TYR is effective in reducing α-syn inclusions, resulting in a lower toxicity and extended life span of treated nematodes. Moreover, TYR delayed α-syn-dependent degeneration of dopaminergic neurons in vivo. TYR treatment also reduced reactive oxygen species level and promoted the expression of specific chaperones and antioxidant enzymes. Overall, our study puts into perspective TYR potential to be considered as nutraceutical that targets pivotal causal factors in PD.

Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites.

Parkinson's disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting 3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1ß in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of Firmicutes, Tenericutes, and Opisthokonta and lower abundance of Proteobacteria at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.

MIND Diet Associated with Reduced Incidence and Delayed Progression of ParkinsonismA in Old Age.

BACKGROUND: In old age, motor impairments including parkinsonian signs are common, but treatment is lacking for many older adults. In this study, we examined the association of a diet specifically developed to promote brain health, called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), to the incidence and progression of parkinsonism in older adults. METHODS: A total of 706 Memory and Aging Project participants aged 59 -97 years and without parkinsonism at baseline were assessed annually for the presence of four parkinsonian signs using a 26-item modified version of the United Parkinson's Disease Rating Scale. Incident parkinsonism was defined as the first occurrence over 4.6 years of follow-up of two or more parkinsonian signs. The progression of parkinsonism was assessed by change in a global parkinsonian score (range: 0-100). MIND, Mediterranean, and DASH diet pattern scores were computed based on a validated food frequency questionnaire including 144 food items. We employed Cox-Proportional Hazard models and linear mixed models, to examine the associations of baseline diet scores with incident parkinsonism and the annual rate of change in global parkinsonian score, respectively. RESULTS: In models adjusted for age, sex, smoking, total energy intake, BMI and depressive symptoms, higher MIND diet scores were associated with a decreased risk of parkinsonism [(HR=0.89, 95% CI 0.83-0.96)]; and a slower rate of parkinsonism progression [(ß= -0.008; SE=0.0037; p=0.04)]. The Mediterranean diet was marginally associated with reduced parkinsonism progression (ß= -0.002; SE=0.0014; p=0.06). The DASH diet, by contrast, was not associated with either outcome. CONCLUSION: The MIND diet created for brain health may be a associated with decreased risk and slower progression of parkinsonism in older adults.

Evidence of neuroprotective effects of saffron and crocin in a Drosophila model of parkinsonism.

Evidence suggests that saffron and its major bioactives exhibit significant neuromodulatory effects in various animal models. However, specific data related to their efficacy to attenuate oxidative stress and neurotoxicity in animal models of Parkinson's disease (PD) are limited. Hence, we investigated the neuroprotective efficacy of saffron methanolic extract (SME) and its active constituent, crocin (CR) employing a Drosophila model of parkinsonism. We focussed on attenuation of Rotenone (ROT)-induced locomotor phenotype, oxidative stress, mitochondrial dysfunction and neurotoxicity in this model. SME and CR-enrichment significantly reduced ROT (500µM) induced mortality, rescued the locomotor phenotype and diminished the enhanced levels of oxidative stress markers in head/body regions of flies. The reduced levels of reduced glutathione (GSH) and total thiols (TSH) resulting from ROT exposure were significantly restored with concomitant enhancement of the antioxidant enzymes activities. Further, ROT-induced mitochondrial dysfunctions (MTT reduction, activities of SDH and NADH-Cyt C reductase (complexes I-III) enzymes) were markedly attenuated by SME/CR enrichment. While ROT elevated the activity of acetylcholinesterase (AChE) in head/body regions, both the treatments caused marked diminution of AChE activity and restored the dopamine levels suggesting their effectiveness to mitigate cholinergic function. Interestingly, SME/CR enrichment significantly delayed the onset of locomotor deficits and extended life span of flies among ROT (50µM)-stressed flies. In a satellite study, flies provided with SME/CR prophylaxis exhibited marked resistance to an acute Paraquat (PQ) challenge as evidenced by the lower incidence of lethality and improved locomotor phenotype. Taken together, the neuroprotective effects of saffron and crocin in the fly model may be largely attributable to its antioxidant action. Based on our findings, we propose that saffron may be exploited as a supplementary therapeutic agent in PD and other oxidative stress mediated neurodegenerative conditions.

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

High intake of folic acid or complex of B vitamins provides anti-Parkinsonism effect: no role for serum level of homocysteine.

Several lines of evidence show that homocysteine (Hcy) levels are increased in blood and CSF of patients with Parkinson's disease. B vitamins are necessary for Hcy metabolism and their deficiencies cause hyperhomocysteinemia and neurodegeneration. In present study, effect of B vitamin supplementation on the severity of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism was investigated. Rats were nourished with B vitamin supplements from 1 month before of stereotaxic injection of 6-OHDA to the end of experiments. Total serum Hcy was measured at the end of experiments to identify its association with Parkinsonism. Both rotational and rotarod tests revealed that supplementation of folic acid, in a dose dependent manner, attenuates severity of Parkinsonism. Supplement of B complex also had beneficial effect and improved motor performance in rotarod test and decreased biased swings in elevated body swing test but had no effect on the apomorphine-induced rotational behavior. Supplement of B(6) attenuated rotational behavior but had no effect on the rotarod performance and swinging behavior. Supplement of B(12) or combination of folic acid with B(6) and B(12) had no effect on the behavioral symptoms of Parkinsonism. Except one group, the levels of Hcy in other vitamin B treated groups were near to that in control group. Surprisingly, Hcy in group of rats that received high intake of folic acid was significantly higher than that in control group. Our results indicate that high intake of folic acid or B complex provides anti-Parkinsonism effect but it is not mediated by lowering plasma Hcy.

Effects of exercise and B vitamins on homocysteine and glutathione in Parkinson's disease: a randomized trial.

BACKGROUND: Individuals with Parkinson's disease (PD) have decreased glutathione levels and elevated homocysteine levels. These substances are considered markers of health, and an inverse relationship has been suggested through the transsulfuration pathway. This experiment tested the effects of exercise and B vitamin supplementation on homocysteine and glutathione levels, and if a relationship was present between these two markers in those with PD. Secondary aims included examining the impact of the interventions on aerobic efficiency and strength. METHODS: Thirty-six subjects were randomly assigned to 4 groups. The Vit group received vitamins B(6), B(12) and folic acid daily for 6 weeks. The Ex group received aerobic and strength training twice weekly for 6 weeks. The Vit + Ex group received both interventions. A control group received no intervention. Subjects were tested prior to and after intervention on the following measures: glutathione and homocysteine levels, strength measures and oxygen consumption. RESULTS: Subjects who received 6 weeks of B vitamin supplementation had lowered homocysteine levels. Subjects who received 6 weeks of exercise training had increased glutathione levels, strength and aerobic capacity. The combination of vitamin and exercise did not yield greater changes than the separate intervention. The control subjects did not change on any measures. CONCLUSION: Positive results were realized with each intervention; however, the expected relationship between glutathione and homocysteine was not found in this sample of subjects with PD. Homocysteine and glutathione levels can be improved independently in individuals with PD with exercise or vitamins B(6), B(12) and folic acid supplementation.

Ethyl-eicosapentaenoate (E-EPA) attenuates motor impairments and inflammation in the MPTP-probenecid mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by hypokinesia, but also mood and cognitive disorders. Neuropathologically, PD involves loss of nigrostriatal dopamine (DA) and secondary non-dopaminergic abnormalities. Inflammation may contribute to PD pathogenesis, evident by increased production of pro-inflammatory cytokines. PD onset has been positively associated with dietary intake of omega-(n)-6 polyunsaturated fatty acids (PUFA). On the other hand, omega-(n)-3 PUFA may benefit PD. One of these n-3 PUFA, eicosapentaenoic acid (EPA), is a neuroprotective lipid with anti-inflammatory properties, but its neuroprotective effects in PD are unknown. Thus, we presently tested the hypothesis that EPA can protect against behavioral impairments, neurodegeneration and inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-probenecid (MPTP-P) mouse model of PD. MPTP-P injections caused hypokinesia in the rotorod and pole test, hyperactivity in the open field, and impaired mice on the cued version (procedural memory) of the Morris water maze. MPTP-P caused a loss of nigrostriatal DA and altered neurochemistry in the frontal cortex and hippocampus. Furthermore, striatal levels of pro-inflammatory cytokines were increased, while the brain n-3/n-6 lipid profile remained unaltered. Feeding mice a 0.8% ethyl-eicosapentaenoate (E-EPA) diet prior to MPTP-P injections increased brain EPA and docosapentaenoic acid (DPA) but not docosahexaenoic acid (DHA) or n-6 PUFA. The diet attenuated the hypokinesia induced by MPTP-P and ameliorated the procedural memory deficit. E-EPA also suppressed the production of pro-inflammatory cytokines. However, E-EPA did not prevent nigrostriatal DA loss. Based on this partial protective effect of E-EPA, further testing may be warranted.

Evaluation of chronic omega-3 fatty acids supplementation on behavioral and neurochemical alterations in 6-hydroxydopamine-lesion model of Parkinson's disease.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been widely associated to beneficial effects over different neuropathologies, but only a few studies associate them to Parkinson's disease (PD). Rats were submitted to chronic supplementation (21-90 days of life) with fish oil, rich in omega-3 PUFAs, and were uni- or bilaterally lesioned with 4microg of the neurotoxin 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle. Although lipid incorporation was evidenced in neuronal membranes, it was not sufficient to compensate motor deficits induced by 6-OHDA. In contrast, omega-3 PUFAs were capable of reducing rotational behavior induced by apomorphine, suggesting neuroprotection over dyskinesia. The beneficial effects of omega-3 PUFAs were also evident in the maintenance of thiobarbituric acid reactive substances index from animals lesioned with 6-OHDA similar to levels from SHAM and intact animals. Although omega-3 PUFAs did not modify the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area, nor the depletion of dopamine (DA) and its metabolites in the striatum, DA turnover was increased after omega-3 PUFAs chronic supplementation. Therefore, it is proposed that omega-3 PUFAs action characterizes the adaptation of remaining neurons activity, altering striatal DA turnover without modifying the estimated neuronal population.

Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model.

While we recently reported the beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a mouse model of Parkinson's disease (PD), the mechanisms of action remain largely unknown. Here, we specifically investigated the contribution of the brain-derived neurotrophic factor (BDNF) to the neuroprotective effect of n-3 PUFA observed in a mouse model of PD generated by a subacute exposure to MPTP using a total of 7 doses of 20mg/kg over 5 days. The ten-month high n-3 PUFA treatment which preceded the MPTP exposure induced an increase of BDNF mRNA expression in the striatum, but not in the motor cortex of animals fed the high n-3 PUFA diet. In contrast, n-3 PUFA treatment increased BDNF protein levels in the motor cortex of MPTP-treated mice, an effect not observed in vehicle-treated mice. The mRNA expression of the high-affinity BDNF receptor tropomyosin-related kinase B (TrkB) was increased in the striatum of MPTP-treated mice fed the high n-3 PUFA diet compared to vehicle and MPTP-treated mice on the control diet and to vehicle mice on the high n-3 PUFA diet. These data suggest that the modulation of BDNF expression contributes, in part, to n-3 PUFA-induced neuroprotection in an animal model of PD.

Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson's disease.

The high-fat ketogenic diet (KD) leads to an increase of blood ketone bodies (KB) level and has been used to treat refractory childhood seizures for over 80 years. Recent reports show that KD, KB and their components (d-beta-hydroxybutyrate, acetoacetate and acetone) have neuroprotective for acute and chronic neurological disorders. In our present work, we examined whether KD protected dopaminergic neurons of substantia nigra (SN) against 6-hydroxydopamine (6-OHDA) neurotoxicity in a rat model of Parkinson's disease (PD) using Nissl staining and tyrosine hydroxylase (TH) immunohistochemistry. At the same time we measured dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum. To elucidate the mechanism, we also measured the level of glutathione (GSH) of striatum. Our data showed that Nissl and TH-positive neurons increased in rats fed with KD compared to rats with normal diet (ND) after intrastriatal 6-OHDA injection, so did DA and its metabolite DOPAC. While HVA had not changed significantly. The change of GSH was significantly similar to DA. We concluded that KD had neuroprotective against 6-OHDA neurotoxicity and in this period GSH played an important role.

Dyskinesias due to intravenous apomorphine abuse in a patient without basal ganglia disorder.

Dyskinesias are known to occur in many patients with Parkinson's disease treated with dopaminergic drugs but to date, drug-induced dyskinesias have not been observed in humans with no underlying basal ganglia disorder. We describe a patient with psychogenic parkinsonism and intravenous apomorphine abuse leading to subsequent choreatiform dyskinesias.