PSYCHONEUROBIOLOGY

As our understanding of the brain has evolved, we have begun to appreciate the intricate interweave of psychiatry, neurology and biochemistry. These fields have overlapped and melded into psychoneurobiology, an integrated medical science that has already yielded important advances in the recognition and treatment of many brain disorders.

Free radicals and oxyradicals have been recognized by psychoneurobiologists as playing an important role in the development and progression of many of these disorders. The brain is particularly susceptible to free radical attack because it generates more oxidative by-products per gram of tissue than any other organ. The brain's main antioxidant is glutathione -it's importance cannot be overstated. Oxidative stress and glutathione are important factors in such various disorders as brain injury, neurodegenerative disease, schizophrenia, Down syndrome and other pathologies dealt with here and in other chapters. 

Psychosocial stress has also been shown to increase oxidative stress. An interesting experiment studying lipid peroxidation levels in older people, some of whom practiced transcendental meditation, showed that meditators suffered less stress and suffered significantly lower levels of lipid peroxidation.

SCHIZOPHRENIA

The Greek translation of schizophrenia is "split mind," and may be misleading. The disorder should not be confused with split personality or multiple personality disorder. It is a different illness characterized by psychosis-a severe disturbance of normal thought, perception, speech and behavior. In mood disorders like anxiety and depression, the ability to discern the real from the imagined is relatively intact. A schizophrenic patient on the other hand often suffers from delusions, auditory or visual hallucinations and paranoid thoughts not based on reality.

Although there is no consensus as to the causes of schizophrenia, most specialists will agree that the symptoms stem from a disturbance-of normal brain chemistry. The tendency seems to run in families, but no single schizophrenia gene has been identified. Psychotherapy by itself is of little value but antipsychotic drugs have been able to reduce relapses by So% and considerably shorten periods of hospitalization. However, these drugs have significant side effects and long-term complications.

It has long been known that glutathione levels are lower in schizophrenic patients. Researchers have consistently demonstrated an increase in their oxidative stress and a decrease in their glutathione status. GSH levels even correspond to the severity of the disease. The Russians N.V and A.V. Govorin further demonstrated that schizophrenics undergoing an acute phase of their disease had higher levels of lipid peroxidation than when in remission. Research scientists such as J. K. Yao and R. D. Reddy of the Veteran's Administration Healthcare System, University of Pittsburgh, suggest that oxidative stress plays an important pathophysiological role in schizophrenia.

A group of neurochemicals called catecholamines are produced normally by the body. They seem to be over-produced in both schizophrenia and Parkinson's disease. The catecholamines break down into ortho-quinonesa group of powerful oxidants. S. Baez's team at the Department of Biochemical Toxicology in Stockholm University examined glutathione's ability to detoxify these metabolites. They concluded that GSH enzymes provided critical protection against the neurodegenerative diseases that are caused or conditioned by these dangerous oxyradicals.

TD. Buckman and A. S. Kling at UCLA School of Medicine conducted a fascinating study. CT scans of schizophrenic patients revealed brain atrophy (shrinkage), suggesting damage to nerve tissue. They linked the extent of atrophy to the degree of glutathione peroxidase deficiency. This suggests a unique function of GSH in preserving the brain from tissue damage in schizophrenics. These findings were corroborated by other centers such as Hahnemann University in Philadelphia.

Antipsychotic drugs require long term use and cause a number of sideeffects. Haldol, Thorazine and other neuroleptics cause a movement disorder called tardive dyskinesia. This results in involuntary puckering of the lips and writhing of the arms and legs and disfigures a large number of patients. It is possible that lipid peroxidation accounts for neuronal damage in this disorer, and scientists have put this theory to the test.

The Scottish team led by K. Brown and A. Reid measured oxidative breakdown products and antioxidant depletion in diskenetic patients and con

firmed the relationship between lipid peroxidation and tardive diskinesia. Other researchers have shown that lipid peroxidation and GSH depletion are aggravated by antipsychotic drugs. Y. Sagara at the Salk Institute in La Jolla, California said that treatments resulting in decreased intracellular GSH would aggravate haloperidol (a neuroleptic antipsychotic) toxicity and may increase a tendency towards tardive dyskinesia.

Researchers J.L. Cadet and L.A. Kahler from the National Institute of Health in Baltimore, S.P. Mahadik and R.E. Scheffer from the Department of Health Behavior, Medical College of Georgia and others have suggested that antioxidants should be used to prevent side effects in patients taking antipsychotics. The Georgia team also showed that oxidative injury increases and GSH-peroxidase levels fall even at the earliest stages of psychosis, and that antioxidants may prevent or slow deterioration.

It appears that sustained GSH levels may slow the progress of schizophrenia and decrease the side effects of some of the drugs used against this disease.

DOWN SYNDROME

Down syndrome is also known as trisomy 21, and inappropriately as mongoloidism because of the distinctive facial characteristics. Ironically, certain areas in the Far East refer to it as `caucausianism.' This congenital disorder occurs during fetal development, when chromosomes divide mistakenly, producing a third 21st chromosome when there should only be two. It is not an inherited trait and is found more frequently in pregnancies of older women. It is relatively common, occurring once in about every 700 births.

Down syndrome leads to several easily recognizable traits including moderate to severe mental retardation, typically flattened facial features, slanted eyes, low-set ears and a large tongue. Less obvious is a tendency toward congenital heart defects, poor vision, leukemia and susceptibility to infectious disease. In a proper environmental setting, Down syndrome patients may lead happy, productive, but generally shorter lives.

Oxidative stress and free radical formation have been studied in Down syndrome. Although there is still debate, certain factors are clear. The gene for an enzyme involved in oxidation/antioxidation reactions called 'superoxide dismutase' (SOD) is located on chromosome 21. Increased SOD activity may overproduce hydrogen peroxide and thus release free radicals. Researchers have observed the heightened demand this places on antioxidant defenses.

Down syndrome patients that make it to an older age seem more prone to the development of Alzheimer's dementia, another neurodegenerative disease. Scientists including those working at the University of California (San Diego) think this is due to changes in free radical metabolism, causing increased destruction of nerve cells. Simple experiments measuring blood serum levels of glutathione reveal significant alterations in GSH activity. More elaborate studies compare GSH activity in Down patients with and without Alzheimer's disease, demonstrating that the already abnormal glutathione defense is further impaired in Down syndrome patients who also suffer from Alzheimer's disease.

An interesting animal experiment published in the August ¹997 issue of Brain Research showed that in brain cells affected by Down syndrome, those with lowered GSH died more quickly. By chemically lowering GSH even further, cell death rates increased. There is no doubt that low GSH levels accelerate brain cell death and that elevated levels slow down neurodegeneration. Intervention with glutathione-enhancing therapies seem helpful.

GSH AND SLEEP

Certain tissues are more susceptible to GSH depletion than others. Measuring glutathione levels in specific areas of the brain of sleep-deprived animals reveals that the thalamus and hypothalamus are particularly susceptible. The vulnerability of these tissues may contribute to some of the functional effects of sleep deprivation.

Oxidized glutathione (GSSG) is an active component of the neurochemical SPS (sleep promoting substance). Researchers at the Tokyo Medical University showed that high levels of oxidized glutathione promote sleep and affect other hypothalamic functions, such as temperature control. The same team also suggests that GSH detoxifies neuronal tissues more actively during certain periods of sleep. This may explain why those taking GSH-enhancing products often report less need for sleep yet feel more energetic.

CASE STUDY

Benjamin, a 44 year-old physician, always wanted a 36-hour day so he'd have time to see his patients, do his research, practice his music, stay in shape and spend more time with his wife and children. Like many other professionals, time and energy were at a premium. Aware of the effects of GSH on the immune system, he took a course of vitamins, selenium and amino acids in the hope of more easily fighting off the viral illnesses to which he was exposed daily. He incorporated indenatured whey protein in to his regimen, wishing to take advantage of its GSH precursors and was soon waking up from 30 to 60 minutes before his alarm went off, and he felt just as refreshed. Now he regularly works later into the evening.

HUNTINGTON^'S DISEASE

Huntington's disease, also known as Huntington's chorea, hereditary chorea, or chronic progressive chorea, is an inherited neurodegenerative movement disorder with progressive intellectual deterioration. It strikes people between the ages of 35 and 5o and advances relentlessly, leading eventually to a physical and mental inability to look after oneself. The term "chorea' refers to the rapid, complex, jerky motions of the face, trunk, and limbs. The associated dementia is accompanied by psychiatric disturbances as well. Traditional treatments are symptomatic and only minimally effective.

These patients seem to be less able than others to deal with oxidative stress. They suffer from increased free radical generation and decreased GSH defenses. Studies depleting glutathione from affected tissue show increased damage to and death of these cells. In the laboratory, antioxidants help cells survive. The neurochemical 3-hydroxykynurenine (3-HK) is found in excessive levels in the brains of Huntington's patients and strongly promotes oxidation. Lab experiments using the GSH-enhancing drug NAC seem to reduce the damage done by 3-HK.

O. Bandmann and a team of neurobiologists at the Institute of Neurology in London, think that an inherent defect in the brain's ability to detoxify neurotoxins may be at the root of Huntington's and Parkinson's diseases. Given the importance of glutathione as an antioxidant, its deficiency in these patients will stimulate many more studies.

CONCLUSION

Many neurological and psychiatric disease processes are characterized by high levels of oxidative stress and free radical formation, as well as abnormalities in glutathione metabolism and antioxidant defenses. Even mental stress has been shown to destabilize oxidant/antioxidant balance in the brain.

Both schizophrenia and the drugs used to treat it lead to GSH abnormalities. Supporting and sustaining glutathione levels may prevent or slow the damage to brain cells typical of this disease. Tardive diskinesia, a longterm side-effect of antipsychotic drug usage, has also been linked to free radical production and depletion of glutathione defense mechanisms. Researchers have proposed that elevated GSH levels may slow the progression of schizophrenia and ease the side effects of medications used to treat it.

Down syndrome patients have an inherent chromosomal abnormality that causes overproduction of abnormal SOD (superoxide dismutase), leading to high levels of oxidative stress that may compound the death of brain cells typical of this congenital disease. The increased rates of Alzheimer's disease in older Down syndrome patients seem to support this theory. Glutathione is the major naturally-occurring antioxidant in the brain and helps combat these oxyradicals.

SEIZURES

Seizures are a group of neurological disorders typified by muscle contractions, twitching and partial or complete loss of consciousness. Specific symptoms depend on the precise location in the brain of chaotic bursts of electrical activity. Seizures range from violent, uncontrollable contractions of the whole body to a subtle and momentary `loss of contact' that may appear to be little more than daydreaming.

Seizures have been referred to as convulsions, fits and epilepsy, as well as by other names that do not accurately reflect the various disorders. Types of seizures include tonic-clonic (grand mal), absence (petit mal), complex-partial (psychomotor, temporal lobe), focal (Jacksonian), and status epilepticus (intractable fits). Not all seizures are epileptic. The most common type of seizure in very young children are called febrile seizures, cause by the rapid onset of fever. Other causes of seizures include stroke or may be a result of injury, tumors, meningitis, hypoglycemia, alcohol withdrawal or other health complications.

Epilepsy-a specific type of seizure with recurrent, unprovoked attacks-is however the most common type, affecting close to three million North Americans-about one in a hundred people, half of them children or adolescents. Of these, one-half fortunately grows out of the disorder.

TREATMENT

Recurrent seizures usually require medication with such oral anticonvulsants as phenobarbital, valproic acid, phenytoin and carbamazine. Patients may need to take these drugs indefinitely. Unfortunately they are not a cure and can have many side-effects, some severe.

Nutritional supplements are used in both conventional and complementary medicine. B-vitamins, particularly B6 (pyridoxine), are effective against certain seizures. Magnesium is also useful, especially in seizures related to high blood pressure. Selenium is used in epileptics, since deficiency of this mineral may intensify the frequency and severity of seizures.

FREE RADICAL DAMAGE IN SEIZURES

Seizures are typified by tremendous bioelectrical activity in the affected area of the brain that generates free radicals in large numbers. Convulsions that provoke loss of consciousness may be accompanied by breathing abnormalities and subsequent oxidative stress. When frequent and/or prolonged, this oxidative stress can damage brain cells. Many studies show that lipid peroxidation (a result of free radical formation) can lead to neuronal damage or destruction of these neurological cells. Moreover, the higher the level of oxidative stress in these tissues, the harder it is to treat. Patients respond less effectively to medication when the ongoing injury and nerve damage provokes further epileptic activity. Canadian researchers at the University of Calgary have even suggested that this continual free radical damage may even result in certain brain tumors.

GLUTATHIONE LEVELS IN SEIZURES

Considerable research has demonstrated that glutathione levels fall significantly in seizure conditions. What is less clear is whether this glutathione deficiency causes seizures, results from them, or both. Nevertheless, the total body glutathione levels of seizure patients are measurably lower than those of normal individuals, and this GSH deficiency is even more noticeable in the affected areas of the brain.

Swiss scientists led by S.G. Mueller studied three groups: patients with active epilepsy, those with controlled epilepsy and non-epileptics. They determined that low glutathione levels more often lead to seizures than result from them. Other research supports this theory by showing how seizures are more frequent or severe when glutathione levels are experimentally lowered. Whatever the specific mechanism, the overall picture shows that glutathione levels fall lower and lower as seizures progress.

Worse still, not only are glutathione levels lowered by seizure activity, the drugs used to treat seizures themselves reduce glutathione levels even further. Japanese researchers H. Ono, A. Sakamoto and N. Sakura showed that both carbamazepine and phenytoin-popular anti-seizure medications-diminish glutathione and leave cells even more susceptible to oxidative damage. Turkish physiologists found the same of valproic acid, another anti-seizure drug.

However, scientists studying childhood seizures at Harvard University found that glutathione levels improved after anticonvulsants were halted and patients were given selenium.

GLUTATHIONE PROTECTS FROM SEIZURES

Since glutathione directly affects the activity of brain cells, it is called a neuromodulator. Japanese scientists K. Abe, K. Nakanishi and H. Saito protected animals from drug-induced seizures by injecting glutathione directly into the fluid of the brain and spinal cord. Canadians at Toronto Western Hospital showed that combined vitamin E and glutathione reduced the number of brain cells damaged after seizure activity. In Texas S.G. Jenkinson, J.M. Jordan and C.A. Duncan were able to protect laboratory animals from seizures and death by injecting them with glutathione, and Italians at the University of Milan successfully prevented seizures caused by isoniazid-a tuberculosis medication-by administering patients with glutathione beforehand.

Several scientists have used n-acetylcysteine (NAC), a powerful glutathione precursor, to treat seizures, and Swedish researchers led by E. Ben-Menachem applied it to patients suffering from progressive myoclonic epilepsy-a particularly hard-to-treat disease that gradually destroys the nervous system. Patients given a daily dose of 6 grams showed marked improvements, and an American team from Gainesville, Florida used NAC, vitamin E, B2, zinc and selenium to treat this type of seizure, obtaining similar improvements.

CONCLUSION

Free radical formation and oxidative stress can be seen as both a cause and a result of seizures, and conditions that diminish glutathione levels-including the use of anti-seizure drugs themselves-may well lower glutathione levels as well. Since glutathione is also itself an anticonvulsant, it may be used as a complementary therapy to both treat and prevent seizures as well as to lessen the adverse effects of conventional drugs.

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