The Biochemical and Cellular Basis for Nutraceutical Strategies to Attenuate Neurodegeneration in Parkinson’s Disease

Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson’s disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc dopaminergic (DAergic) neurons and decay of the striatal tract. While genetic mutations or environmental toxins can precipitate pathology, progressive degenerative succession involves a gradual decline in DA neurotransmission/synaptic uptake, impaired oxidative glucose consumption, a rise in striatal lactate and chronic inflammation. Nutraceuticals play a fundamental role in energy metabolism and signaling transduction pathways that control neurotransmission and inflammation. However, the use of nutritional supplements to slow the progression of PD has met with considerable challenge and has thus far proven unsuccessful. This review re-examines precipitating factors and insults involved in PD and how nutraceuticals can affect each of these biological targets. Discussed are disease dynamics (Sections 1 and 2) and natural substances, vitamins and minerals that could impact disease processes (Section 3). Topics include nutritional influences on α-synuclein aggregation, ubiquitin proteasome function, mTOR signaling/lysosomal-autophagy, energy failure, faulty catecholamine trafficking, DA oxidation, synthesis of toxic DA-quinones, o-semiquinones, benzothiazolines, hyperhomocyseinemia, methylation, inflammation and irreversible oxidation of neuromelanin. In summary, it is clear that future research will be required to consider the multi-faceted nature of this disease and re-examine how and why the use of nutritional multi-vitamin-mineral and plant-based combinations could be used to slow the progression of PD, if possible

Rapeseed oil and magnesium manipulations affect the seizure threshold to kainate in mice*

We have previously shown that the drop in N-methyl-D-aspartate (NMDA)-induced seizure threshold caused by nutritional magnesium deprivation responded well to the w-3 polyunsaturated fatty acid (PUFA) alpha-linolenate (ALA) (5% rapeseed oil) diet when compared to w-6 PUFA diet. In the present work, kainate-induced seizures are shown to be also exacerbated by magnesium deprivation. ALA diet better attenuates this seizure exacerbation when compared to the non-ALA diet. The reversion of the drop in kainate seizure threshold induced in these conditions by magnesium administration was, however, better under the non-ALA diet in comparison with the ALA diet. Taken as a whole, present data indicate that kainate like NMDA brain injury is attenuated by ALA diet. On the other hand, the relative failure of ALA diet to potentiate reversion induced by magnesium might suggest that magnesium and ALA protections are not additive

Rapeseed oil and magnesium manipulations affect the seizure threshold to kainate in mice

We have previously shown that the drop in N-methyl-D-aspartate (NMDA)-induced seizure threshold caused by nutritional magnesium deprivation responded well to the w-3 polyunsaturated fatty acid (PUFA) alpha-linolenate (ALA) (5% rapeseed oil) diet when compared to w-6 PUFA diet. In the present work, kainate-induced seizures are shown to be also exacerbated by magnesium deprivation. ALA diet better attenuates this seizure exacerbation when compared to the non-ALA diet. The reversion of the drop in kainate seizure threshold induced in these conditions by magnesium administration was, however, better under the non-ALA diet in comparison with the ALA diet. Taken as a whole, present data indicate that kainate like NMDA brain injury is attenuated by ALA diet. On the other hand, the relative failure of ALA diet to potentiate reversion induced by magnesium might suggest that magnesium and ALA protections are not additive

Ketogenic diet and astrocyte/neuron metabolic interactions

The ketogenic diet is an anticonvulsant diet enriched in fat. It provides the body with a minimal protein requirement and a restricted carbohydrate supply, the vast majority of calories (more than 80-90%) being given by fat. Though anticonvulsant activity of ketogenic diet has been well documented by a large number of experimental and clinical studies, underlying mechanisms still remain partially unclear. Astrocyte-neuron interactions, among which metabolic shuttles, may influence synaptic activity and hence anticonvulsant protection. The astrocyte-neuron metabolic shuttles may be themselves influenced by the availability in energetic substrates such as hydrates of carbon and fats. Historically, ketogenic diet had been designed to mimic changes such as ketosis occurring upon starvation, a physiological state already known to exhibit anticonvulsant protection and sometimes referred to as “water diet”. For this reason, a special attention should be paid to metabolic features shared in common by ketogenic diet and starvation and especially those features that might result in anticonvulsant protection. Compared to feeding by usual mixed diet, starvation and ketogenic diet are both characterised by increased fat, lowered glucose and aminoacid supplies to cells. The resulting impact of these changes in energetic substrates on astrocyte/neuron metabolic shuttles might have anticonvulsant and/or neuroprotective properties. This is the aim of this communication to review some important astrocyte/neuron metabolic interactions (astrocyte/neuron lactate shuttle, glutamateinduced astrocytic glycolysis activation, glutamate/glutamine cycle along with the neurovascular coupling) and the extent to which the way of their alteration by starvation and/or ketogenic diet might result in seizure and/or brain protection

Ketogenic diet and astrocyte/neuron metabolic interactions

The ketogenic diet is an anticonvulsant diet enriched in fat. It provides the body with a minimal protein requirement and a restricted carbohydrate supply, the vast majority of calories (more than 80-90%) being given by fat. Though anticonvulsant activity of ketogenic diet has been well documented by a large number of experimental and clinical studies, underlying mechanisms still remain partially unclear. Astrocyte-neuron interactions, among which metabolic shuttles, may influence synaptic activity and hence anticonvulsant protection. The astrocyte-neuron metabolic shuttles may be themselves influenced by the availability in energetic substrates such as hydrates of carbon and fats. Historically, ketogenic diet had been designed to mimic changes such as ketosis occurring upon starvation, a physiological state already known to exhibit anticonvulsant protection and sometimes referred to as “water diet”. For this reason, a special attention should be paid to metabolic features shared in common by ketogenic diet and starvation and especially those features that might result in anticonvulsant protection. Compared to feeding by usual mixed diet, starvation and ketogenic diet are both characterised by increased fat, lowered glucose and aminoacid supplies to cells. The resulting impact of these changes in energetic substrates on astrocyte/neuron metabolic shuttles might have anticonvulsant and/or neuroprotective properties. This is the aim of this communication to review some important astrocyte/neuron metabolic interactions (astrocyte/neuron lactate shuttle, glutamateinduced astrocytic glycolysis activation, glutamate/glutamine cycle along with the neurovascular coupling) and the extent to which the way of their alteration by starvation and/or ketogenic diet might result in seizure and/or brain protection

Ketogenic diet and astrocyte/neuron metabolic interactions

The ketogenic diet is an anticonvulsant diet enriched in fat. It provides the body with a minimal protein requirement and a restricted carbohydrate supply, the vast majority of calories (more than 80-90%) being given by fat. Though anticonvulsant activity of ketogenic diet has been well documented by a large number of experimental and clinical studies, underlying mechanisms still remain partially unclear. Astrocyte-neuron interactions, among which metabolic shuttles, may influence synaptic activity and hence anticonvulsant protection. The astrocyte-neuron metabolic shuttles may be themselves influenced by the availability in energetic substrates such as hydrates of carbon and fats. Historically, ketogenic diet had been designed to mimic changes such as ketosis occurring upon starvation, a physiological state already known to exhibit anticonvulsant protection and sometimes referred to as “water diet”. For this reason, a special attention should be paid to metabolic features shared in common by ketogenic diet and starvation and especially those features that might result in anticonvulsant protection. Compared to feeding by usual mixed diet, starvation and ketogenic diet are both characterised by increased fat, lowered glucose and aminoacid supplies to cells. The resulting impact of these changes in energetic substrates on astrocyte/neuron metabolic shuttles might have anticonvulsant and/or neuroprotective properties. This is the aim of this communication to review some important astrocyte/neuron metabolic interactions (astrocyte/neuron lactate shuttle, glutamateinduced astrocytic glycolysis activation, glutamate/glutamine cycle along with the neurovascular coupling) and the extent to which the way of their alteration by starvation and/or ketogenic diet might result in seizure and/or brain protection

Is chronic rapeseed oil diet more neuroprotective than chronic corn/sunflower diet?

Polyunsaturated fatty acids (PUFA) and specifically omega3 have been shown to exert a potent protecting effect on both cardiac and neuronal functions. Rapeseed oil contains 9% of alphalinolenic acid (18-3n-3, ALA), whereas corn and sunflower oils (18:2n-6, linoleic acid rich) do not. The aim of the present study was to compare in mice the putative protective effects of ALA, by testing two chronic diets containing either rapeseed oil (ALA rich) or a corn/sunflower blend (devoided of ALA) using an epilepsy model, allowing the detection of neurotoxic or neuroprotective activities: the MDDAS test (Magnesium Deficiency-Dependent Audiogenic Seizure test). After a 30 day-Mg-deprivation period, neuronal hyperexcitability appeared only in the corn/sunflower fed group, suggesting a protecting effect of the rapeseed oil. The number of convulsive mice was twice reduced in the rapeseed group and all of them recovered whereas in the corn/sunflower group all the mice had seizures and 43% died. The pattern of seizures with the rapeseed diet showed an increase in the first two step durations (latency and wild running), and a non significant slight decrease in the third (convulsions) and the fourth (recovery) ones. These results suggest a GABAergic-like effect. The increases in the first 2 phases were also indicative of a likely effect on Na+ channels, which was also observed using the maximum electroshock seizure test. These preliminary results indicate that adapted chronic dietary intake of rapeseed oil, an ALA rich monounsaturated oil, could help to control neuronal disorders as here shown in our model of magnesium-deficient mice

Is chronic rapeseed oil diet more neuroprotective than chronic corn/sunflower diet?

Polyunsaturated fatty acids (PUFA) and specifically omega3 have been shown to exert a potent protecting effect on both cardiac and neuronal functions. Rapeseed oil contains 9% of alphalinolenic acid (18-3n-3, ALA), whereas corn and sunflower oils (18:2n-6, linoleic acid rich) do not. The aim of the present study was to compare in mice the putative protective effects of ALA, by testing two chronic diets containing either rapeseed oil (ALA rich) or a corn/sunflower blend (devoided of ALA) using an epilepsy model, allowing the detection of neurotoxic or neuroprotective activities: the MDDAS test (Magnesium Deficiency-Dependent Audiogenic Seizure test). After a 30 day-Mg-deprivation period, neuronal hyperexcitability appeared only in the corn/sunflower fed group, suggesting a protecting effect of the rapeseed oil. The number of convulsive mice was twice reduced in the rapeseed group and all of them recovered whereas in the corn/sunflower group all the mice had seizures and 43% died. The pattern of seizures with the rapeseed diet showed an increase in the first two step durations (latency and wild running), and a non significant slight decrease in the third (convulsions) and the fourth (recovery) ones. These results suggest a GABAergic-like effect. The increases in the first 2 phases were also indicative of a likely effect on Na+ channels, which was also observed using the maximum electroshock seizure test. These preliminary results indicate that adapted chronic dietary intake of rapeseed oil, an ALA rich monounsaturated oil, could help to control neuronal disorders as here shown in our model of magnesium-deficient mice