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Life Extension Magazine

LE Magazine January 2001

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Page 4 of 5

 

Excitotoxicity and stroke

A pathology common to many neurological disorders is excitatory toxicity, or excitotoxicity. It is caused by an excess of, or excessive sensitivity to, glutamate—the main excitatory neurotransmitter. Excitotoxicity triggers a cascade of events including membrane polarization, ending in cell death. Oxidative stress and excitotoxicity are thought to reinforce each other in a vicious cycle.

It is probable that excitotoxic complications determine the long-term effects of stroke. In Alzheimer's disease, laboratory experiments show that amyloid-beta sensitizes cultured neurons to excitotoxic death (Doble A, 1999).

Carnosine and glutamate are found together in presynaptic terminals in the brain. Experimental evidence shows that carnosine protects cells against excitotoxic death, supporting the notion that carnosine serves the same purpose in the brain. An interesting Russian study showed that rat cerebellar cells incubated in carnosine were resistant to excitotoxic cell death from the glutamate analogs NMDA and kainite (Boldyrev A et al., 1999).

Copper and zinc

Copper and zinc are neurological double-edged swords. While the body cannot live without them, new research from Florida State University confirms that they can also be neurotoxic (Horning MS et al., 2000). Abnormal copper-zinc metabolism is implicated in Alzheimer's disease, stroke, seizures and many other diseases with neurological components.

Copper and zinc are thought to modulate synaptic transmission, but are rapid neurotoxins at the concentrations reached when they are released from synaptic terminals. The brain must buffer these metals so that they can perform their functions without neurotoxicity. The new research on copper and zinc toxicity shows that carnosine provides that buffering action.

Copper and zinc in Alzheimer's disease

Copper and zinc contribute to amyloid-beta formation and toxicity through a host of mechanisms. When amyloid-beta aggregates, as it does in plaque formation, it becomes more neurotoxic. Laboratory experiments show that tiny amounts of zinc and especially copper cause amyloid-beta to aggregate.

The mildly acidic environment characteristic of Alzheimer's disease dramatically increases aggregation of amyloid-beta by copper ions (Atwood CS et al., 1998). Inflammation, thought to aggravate and possibly cause Alzheimer's disease, also creates an acidic environment. Moreover, the acidosis, inflammation and disturbed
energy metabolism associated with the disease are thought to increase copper and zinc levels, thus setting the stage for accelerated formation of amyloid-beta plaques (Atwood CS et al., 1998).

In the presence of copper ions amyloid-beta is thought to generate hydrogen peroxide, which can then react with iron or copper ions to produce highly neurotoxic hydroxyl radicals. In addition, copper forms complexes with amyloid-beta that markedly potentiate amyloid-beta neurotoxicity (Huang X et al., 1999).

The brain must buffer copper and zinc so that they can perform their functions without inducing toxicity. New research show that copper and zinc toxicity in the brain can be buffered by carnosine. (Horning MS et al., 2000)

When scientists exposed rat neurons to physiological concentrations of copper or zinc, the neurons died. However carnosine, at a modest physiological concentration, protected the neurons from the toxic effects of these metals (Horning MS et al., 2000).

A spate of recent research papers point up the central role of copper and zinc in the development of Alzheimer's disease. Levels of these metals are elevated in the Alzheimer's disease brain, even more so in
the amyloid-beta plaques (“senile plaques”) which are the central feature of the disease (see the sidebar “Copper and Zinc in Alzheimer’s disease”).

A groundbreaking study discovered that chelators of copper and zinc solubilize (dissolve) aggregates of amyloid-beta in post-mortem human tissue samples from the brains of Alzheimer's disease patients (Cherny RA et al., 1999). The researchers conclude, “agents that specifically chelate copper and zinc ions but preserve Mg(II) and Ca(II) may be of therapeutic value in Alzheimer's disease.”

Carnosine fits this profile, offering in addition pH buffering and hydroxyl radical scavenging actions. Not only does carnosine chelate copper and zinc, but the presence of copper and zinc ions enhances carnosine's potency as a scavenger of the superoxide radical (Gulyaeva NV, 1987). This is especially significant since amyloid-beta damages brain endothelial (blood vessel wall) cells quickly and at low concentrations by generating oxidative stress, particularly in the form of superoxide radicals (Thomas T et al., 1996). Microvascular damage is the harbinger of Alzheimer's disease, precdeding its other pathological features.

One theory of Alzheimer's disease development holds that the distorted microvasculature seen in the disease is the primary cause of Alzheimer's, impairing delivery of nutrients to the brain (de la Torre JC, 1997). An experiment on rat brain endothelium shows that carnosine prevents this damage. When endothelium was incubated with amyloid-beta and a physiological concentration of carnosine, damage to endothelial cells was significantly reduced or completely eliminated (Preston JE et al., 1998).

In another experiment carried out by the same British team, carnosine protected brain endothelial cells from damage by MDA (malondialdehyde), a toxic product of lipid peroxidation. Carnosine inhibited protein carbonylation and cross-linking, while protecting cellular and mitochondrial function (Hipkiss AR et al., 1997). A third experiment showed that carnosine also protects these cells against the toxicity of acetaldehyde, which is produced when alcohol is metabolized (Hipkiss AR et al., 1998).

AGEs and amyloid plaque

Carnosine thus works along multiple pathways that prevent the formation of amyloid plaque, inhibit amyloid-beta toxicity and promote amyloid plaque breakdown in laboratory experiments. An examination of how the plaques form reveals an additional pathway.

Stroke Neuroprotection

Two Russian studies show that carnosine protects the brain in simulated strokes (Stvolinsky SL et al., 1999; Boldyrev AA et al., 1997). In the first experiment, rats were exposed to low pressure hypoxia. Rats given carnosine beforehand were able to keep standing and breathing almost twice as long as the others. After the hypoxia, carnosine treated rats were able to stand after 4.3 minutes, as compared to 6.3 minutes for the untreated rats.

The second study simulated stroke through arterial occlusion. Rats treated with carnosine displayed a more normal EEG, less lactate accumulation (a common measure of injury severity), and better cerebral blood flow restoration. The study also demonstrated that carnosine preserves activity of a key enzyme, Na/K-ATPase, which extracts energy stored in ATP to drive the cellular sodium pump. Na/K-ATPase inhibition has been found to correlate with edema in the ischemic (blood-deprived) region.

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The first step in plaque formation is thought to be the slow and reversible development of a nucleus, followed by a phase of rapid cross-linking and growth. AGEs (see “Glycation and AGE formation”) accelerate both these steps by cross-linking soluble monomers to form insoluble aggregates. In fact, researchers hypothesize that the crucial step in the formation of a stable amyloid nucleus is the cross-linking of amyloid-beta by AGEs (Munch G et al., 1997).

These researchers found that amyloid-beta cross-linking was inhibited by three AGE inhibitors: the pharmaceuticals aminoguanadine and tenilsetam, and carnosine. Tenilsetam has demonstrated clinical benefit in Alzheimer's disease. The researchers incubated amyloid-beta with fructose, which is abundant in the brain and cross-links proteins up to ten times faster than glucose. Soluble amyloid disappeared as aggregates formed, driven by AGE cross-linking. All three AGE inhibitors prevented cross-linking of amyloid-beta, keeping nearly 100% of it in a soluble form.

Given the brain's dependence upon glucose for energy metabolism and the unusually high ratio of fructose to glucose in the brain (about 1:4, compared to 1:20 in plasma), it seems likely that carnosine serves as a natural glycation inhibitor in the brain.

We have seen that carnosine extends life span at the level of the cell and of the organism. It is equally beneficial to dividing cells and non-dividing cells such as neurons. Moreover, like CoQ10, nature appears to have anticipated us in the purposes carnosine naturally serves in the body.

Surpassing the many supplements that address few and limited aging mechanisms, carnosine stands out as the most promising pluripotent life extension discovery since The Life Extension Foundation introduced Coenzyme Q10 to the American public nearly twenty years ago.

 

References on Page 5

 

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