Neuroprotective effects of vitamins C and E against epilepsy-induced neuronal death

Epilepsy,Neuroprotectors — Tags: , , , , — 7:49 am

Epilepsy is thought to be associated with oxidative stress, which play its role in the seizures-induced neuronal death (1, 2). On the other hand, the brain, due to a high content of polyunsaturated fatty acids, is an easy target for the peroxidation. Luckily, it has neuroprotective systems such as superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione (3, 4).

Exogenous antioxidants like vitamin E and C, can inhibit the neuronal damage provoced by lipid peroxidation during seizures and prevent the increase in brain free fatty acid levels, suggesting that the protection may be mediated by, for example, increase of hippocampal catalase activity (5). Vitamin C significantly decreased the lipid peroxidation after seizures induced by cholinergic agonist pilocarpine supporting the idea of interaction of the C and E vitamins with catalase activity to produce neuronal protection amd to decrease the lipid peroxidation level (6).

When oxidative damage accumulates over  years, it may account for the increased incidence of neurodegenerative diseases in aged populations. The mechanisms of neuronal degeneration in these cases remain unknown and this is a major obstacle in the development of effective therapies targeting the causes of the diseases.

Sources

  1. Neurosci Lett 420 (2007), pp. 76–79
  2. Neurosci Lett 291 (2000), pp. 179–182
  3. Cell signaling and neurotoxic events. In: L.W. Chang, Editor, Principles of Neurotoxicology, Marcel Dekker, New York (1994), pp. 475–493
  4. Neurosci Lett 8 (2007), pp. 76–79
  5. Epilepsy Res 46 (2001), pp. 121–128
  6. Pharmac Biochem & Behavior, Volume 89, Issue 1, March 2008, Pages 1-5

Toxic glycolysis and brain aging

Glucose,Hormesis,Theories — Tags: , , , , , , — 8:29 am

Related article: Prescription-strength stress as a medicine

The intermittent glycolysis during fasting, physical exercise, and stress may delay senescence by lowering intracellular concentration of methylglyoxal, a common intermediate in the Maillard reaction (glycation).

A simple logic allows to imagine that a situation when food is available to an animal at all times and in any quantities should be very seldom. In real life, there are seasons when food is abundant and seasons when it’s scarce. To smoothen the energy delivery to vital organs, there all kind of depots, most famous (or rather infamous for us human beings in Western societies) is the fat depot, having practically unlimited capacity. There is clinical evidence that a human body can save in this depot enough energy to feed itself for a year. Vitamins and electrolyte fluids should be adequately supplied of course, but no calories enter the body – and it survives!

The opposite situation, when animals are allowed to eat as much as they can, as often as they can, is called ad libitum (AL). In experiments on beneficial effects of calorie restriction (CR), the food intake in the AL situation is taken for 100% and then different percentages of restrictions are applied to see CR effectiveness to slow down the process of aging, especially brain aging.

In an early study of the energy metabolism McCarter and Palmer (1) interesting differences were revealed, between rats fed CR diets and those fed the same food but AL. Although in both groups energy metabolism was mostly glycolytic, taping in carbohydrate metabolic way, CR very soon after feeding switched to using their bodies’ fat reserves with their glycolysis suppressed, while the AL group maintained practically non-stop glycolysis.

So it’s been suggested that that the beneficial effects of CR could be due to suppression of glycolysis and in experiments of Walker et al. (2) and Partridge and Brand (3) the question of whether the shortened life-span of AL animals results from some metabolic toxicity, specifically whether glycolysis is deleterious but possibly hormetic (4)

The hormesis hypotheses by Masoro (5) and Sinclair (6) suggests that intermittent stress may induce synthesis of long-term protective functions. Glycolytic intermediates dihydroxyacetone- and glyceraldehyde-3-phosphates are form methylglyoxal (MG), which is potentially toxic.

Hipkiss (7) suggested that non-stop glycolysis is deleterious due to the generation of MG, but periods of glycolysis interruption could be hormetic. MG damages mitochondria and induces a pro-oxidant state characteristics to cellular aging. The decreased glycolysis during CR may delay senescence by lowering intracellular MG concentration compared to AL animals.

Sources

1. Am. J. Physiol. 1992 263, E448-E452

2. Mech. Ageing Dev. 2005 126, 929-937

3. Mech. Ageing Dev. 2005 126, 911-912

4. Hormesis – An effect in which a toxic substance acts like a stimulant in small doses, but it is an inhibitor in large doses.

5. Mech. Ageing Dev. 2005 126, 913-922

6. Mech. Ageing Dev. 2005 126, 987-1002.

7. Mech. Ageing Dev. 2006 127 8-15

Neuroprotective effects of Coenzyme Q10

Neurodegenerative diseases,Neuroprotectors — Tags: , , — 6:00 am

Related: Is Q10 a fitness-enhancing or an anti-aging supplement in the long run?

“Several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy.”
Meredith Spindler, M Flint Beal, and Claire Henchcliffe. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009; 5: 597–610
“There is ample evidence showing involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders, therefore, one would predict that agents that alleviate mitochondrial dysfunction could be beneficial and exert neuroprotective effects. Several bioenergetic agents that improve mitochondrial function including creatine, coenzyme Q10 (CoQ10), nicotinamide, riboflavin and lipoic acid are being tested for their neuroprotective efficacy in neurodegenerative disorders. Among them, creatine and CoQ10 are in clinical trials for PD, HD and AD.”
Rajnish K. Chaturvedi and M. Flint Beal. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci. 2008 December; 1147: 395–412
“…combination therapy using CoQ10 and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson’s disease and HD.”
Lichuan Yang  et al., Combination therapy with Coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s Diseases. J Neurochemistry, 109, 5, 1427–1439, 2009
“…a synthetic analog of CoQ10, idebenone, has been investigated in clinical trials for its ability to inhibit lipid peroxidation. Although several smaller studies reported beneficial effects on memory and attention after several months of treatment, a larger study reported no effect in slowing disease progression.”
Magali Dumont, M. Flint Beal. Neuroprotective strategies involving ROS in Alzheimer disease. Free Radical Biology and Medicine, 2011, online ahead of print
“These data demonstrate that in addition to reducing intracellular deposition of A-beta, CoQ10 can also reduce plaque pathology. Our study further supports the use
of CoQ10 as a therapeutic candidate for AD.”
Xifei Yang et al., Coenzyme Q10 Reduces β-Amyloid Plaque in an APP/PS1
Transgenic Mouse Model of Alzheimer’s Disease. Mol Neurosci (2010) 41:110–113
Abbreviations

PD: Parkinson’s disease;
HD: Huntington’s disease;
AD: Alzheimer’s disease;
A-beta – beta-Amyloid peptide

The MMM of aging: mood, memory, movement

Alzheimer's,Dementia,Neurodegenerative diseases,Neuroprotectors,Parkinson's — Tags: , , , , — 6:55 am

“Thinking, Moving, Feeling”: What Do They Have in Common?

This question opens a review of age-related declines, their inter-relationships, mechanisms, and the ways to postpone if not avoid them. The authors discuss the occurrence of depression and mood disorders during normal, premature or pathological aging, reminding that the usual suspects – serotonin and norepinephrine – indeed decline as people age as well as in Alzheimer’s and Parkinson’s diseases (A, Granholm et al., Mood, Memory and Movement: An Age-Related Neurodegenerative Complex? Curr Aging Sci. 2008 July ; 1(2): 133–139.)

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The seven effects of ketone bodies making them powerful neuroprotectors

Ketone bodies,Neuroprotectors — Tags: , , , — 9:27 am

There are seven traits allowing ketones to serve as neuroprotectors during brain damage:

  1. they require only three steps to enter the Krebs cycle (footnote a) – compare with 9 steps obligatory for glucose;
  2. they cause  inhibition of glycolysis, thus decreasing free radical formation;
  3. they increase production of ATP (footnote b);
  4. they increase mitochondrial energy efficiency;
  5. they increase antioxidant activity of glutathione peroxidase (footnote c);
  6. they spare pyruvate from processing in the Krebs cycle

Source: Journal of Cerebral Blood Flow & Metabolism (2008) 28, 1–16

Footnotes
a) The Krebs cycle or the citric acid cycle is a metabolic pathway involved in the conversion (“burning”) of carbohydrates, fats and proteins into CO2 and H2O to generate energy in the form that can be used by living organisms.
b) ATP: Adenosine Triphosphate, the ultimate “energy molecule”.
c) Glutathione peroxidase: a powerful scavenger of free radicals.
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