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.

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

Fish oil provides robust and sustained memory recovery after cerebral ischemia: influence of treatment regimen.

We previously reported that long-term treatment with fish oil (FO) facilitates memory recovery after transient, global cerebral ischemia (TGCI), despite the presence of severe hippocampal damage. The present study tested whether this antiamnesic effect resulted from an action of FO on behavioral performance itself, or whether it resulted from an anti-ischemic action. Different treatment regimens were used that were distinguished from each other by their initiation or duration with regard to the onset of TGCI and memory assessment. Naive rats were trained in an eight-arm radial maze, subjected to TGCI (4-VO model, 15 min), and tested for memory performance up to 6 weeks after TGCI. Fish oil (docosahexaenoic acid, 300 mg/kg/day) was given orally according to one of the following regimens: regimen 1 (from 3 days prior to ischemia until 4 weeks post-ischemia), regimen 2 (from 3 days prior to ischemia until 1 week post-ischemia), and regimen 3 (from week 2 to week 5 post-ischemia). When administered according to regimens 1 and 2, FO abolished amnesia completely. This effect persisted for at least 5 weeks after discontinuing the treatment. Such an effect did not occur, however, in the group treated according to regimen 3. Hippocampal and cortical damage was not alleviated by FO. The present results demonstrate that FO-mediated memory recovery (or preservation) following TGCI is a reproducible, robust, and long-lasting effect. Moreover, such an effect was found with a relatively short period of treatment, provided it covered the first days prior to and after ischemia. This suggests that FO prevented amnesia by changing some acute, ischemia/reperfusion-triggered process and not by stimulating memory performance on its own.

Dietary carnitine supplements slow disease progression in a putative mouse model for hereditary ceroid-lipofuscinosis.

The childhood ceroid-lipofuscinoses are a group of autosomal recessively inherited disorders characterized by massive accumulation of autofluorescent lysosomal storage bodies in neurons as well as other cell types. The storage body accumulation is accompanied by severe degeneration of the central nervous system that results in blindness, cognitive and psychomotor degeneration, and premature death. On the basis of pathologic and biochemical criteria, a hereditary disease in the mnd mouse strain has been proposed as a model for certain types of human ceroid-lipofuscinosis. Experimental evidence suggests that the storage body accumulation in humans with juvenile and late-infantile ceroid-lipofuscinosis is linked to altered carnitine biosynthesis. On the basis of the latter observation, a study was performed to determine whether dietary carnitine supplements could slow the disease progression in the mnd mouse model. Carnitine supplementation begun at 4 weeks of age did not slow the retinal degeneration that is characteristic of this disease. It did, however, significantly elevate brain carnitine levels, slow the accumulation of autofluorescent storage bodies in brain neurons, and prolong the lifespans of the treated animals. These findings suggest that there is a link between carnitine biosynthesis and the disease pathology and indicate that carnitine supplementation may be beneficial in slowing the disease progression in humans with certain types of hereditary ceroid-lipofuscinosis.