NONI IN NEURODEGENERATIVE DISEASES

1. NONIINNEURODEGENERATIVE DISEASES Parkinson’s Disease Alzheimer’s disease Senile Dementia Amyotrophic Lateral Sclerosis (ALS)

2. FREE RADICALS AND OXIDATIVE STRESS IN NEURODEGENERATIVE DISEASES:RELEVANCE OF INDIAN NONI, A POWERFUL ANTIOXIDANTS AND NATURAL NUTRITIONAL SUPPLEMENTS ABSTRACT Oxidants and antioxidants plays an important role in maintaining a balance between free radicals and the antioxidant system of the body. Free radicals are created either by the normal metabolism process or derived from environmental sources. A complex natural endogenous antioxidant system exists in our body which is responsible for prevention of damage by pro oxidants or free radicals. Impaired endogenous antioxidant system favors accumulation of free radicals, which not only induces the process of lipid peroxidation but also plays a central role in neurodegeneration. Neurodegenerative disorders remains always an important source of morbidity and suffering for the human society. The free-radical-mediated oxidative injury to the nervous system like strokeor traumaand various chronic neurodegenerative disorders are being recognized.

3. The increased incidence of neurodegenerative diseases like parkinson’s diseases, Alzheimer’s disease, lateral sclerosis, senile dementia etc may be attributed to a pro-oxidative environment caused by smoking, alcohol abuse, ultra-violet ray radiations, air pollution, pressure packed life style as well as inappropriate nutrition. The dependence of disease severity by an imbalance between oxidants and natural defenses suggests that oxidative stress plays a pivotal role in the progression of neurodegenerative diseases and could serve as a useful target for treatment. A high antioxidant food supplement can prevent or reduce the degenerative changes in brain and spinal cord by enhancing or modifying the body’s endogenous antioxidant system and also by providing exogenous antioxidants to the body. Indian Noni contains all the antioxidant vitamins, important trace minerals and rich with phytochemicals. The synergistic actions of all those ingredients just make Indian Noni a very powerful antioxidant food supplement that may help in prevention and/or therapeutic intention in various neurodegenerative diseases. It is our attempt through this clinical trial to put forth the evidence for involvement of free radicals in pathophysiology of neurodegenerative diseases and the action of Indian Noni in or therapeutic purposes of various neurodegenerative diseases.

4. ROLE OF INDIAN NONI IN CHRONIC NEURODEGENARATIVEDISEASES NEURODEGENERATIVE DISEASES: AN OVERVIEW Neurodegenerative disease is a condition which affects brain function. It result from deterioration of neurons. It is a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have many different etiology. Many are hereditary, some are secondary to toxic or metabolic processes, and others result from infections. The free-radical-mediated oxidative injury to neurons is one of the major cause of various neurodegenerative diseases. Due to the prevalence, morbidity, and mortality of the neurodegenerative diseases, they represent significant medical, social, and financial burden on the society. Neuropathologically, these are characterised by abnormalities of relatively specific regions of the brain and specific populations of neurons. The degenerating neuron clusters in the different diseases determine the clinical phenotype of that particular illness. Recent investigations in medical genetics have identified specific genes for various neurodegenerative disorders

5. SOME COMMON NEURO DEGENERATIVE DISEASES • Parkinson’s Disease • Alzheimer’s disease • Frontotemporal Dementia • Amyotrophic Lateral Sclerosis (ALS)

6. PARKINSON’S DISEASE Parkinson's disease may arise as a combined consequence of the ongoing aging process coupled with free radical’s damaging effects that accelerate the process of substantial nigral’s cells death in brain Neuropathological changes : The major neuropathologic findings in PD are loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies.

8. ALZHEIMER’S DISEASE Alzheimer's disease is the most common form of dementia among older people. It involves the parts of the brain that control thought, memory, and language. Some of the deterioration may be related to the loss of neurotransmitters –the acetylcholine. Neuropathological changes : Generalised cortical atrophy with shrinkage of the amygdala and hippocampus. Selective dysfunction and death of neocortex, hippocampus, amygdala, basal forebrain, and brainstem.The deposition of an abnormal protein outside nerve cells in the form of amyloid. These are called diffuse plaques. Amyloid also accumulates in the walls of small blood vessels in the brain. This is amyloid angiopathy. Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced.

10. SENILE DEMENTIA Senile Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. The affected areas may be memory, attention, language and problem solving, although particularly in the later stages of the condition, affected persons may be disoriented in time (not knowing what day, week, month or year it is), disoriented in place (not knowing where they are) and disoriented in person (not knowing who they are). Most common causes are • Alzheimer's disease • Vascular dementia (also known as multi-infarct dementia) • Dementia with Lewy bodies • Frontotemporal lobar degeneration (FTLD), including Pick's diseases

11. AMYOTROPHIC LATERAL SCLEROSIS (ALS) Amyotrophic lateral sclerosis is a chronic, progressive, almost invariably fatal neurological disease. It is marked by gradual degeneration of the neurons in the central nervous system that control voluntary muscles movement. The disorder causes muscles weakness and atrophy throughout the body. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away i.e atrophied, and have fasciculations because of denervation

13. THE FREE RADICALS Free radicals are highly reactive molecules having unpaired electrons in its outer sphere. Generation of free radicals or highly Reactive Oxygen Species (ROS) is an integral feature of normal cellular function like mitochondrial respiratory chain, phagocytosis, arachidonic acid metabolism, ovulation, and fertilisation. Their production however, multiplies several folds during pathological conditions. Types of free radicals or reactive oxygen species (ROS) include the hydroxyl radical (OH.), the superoxide radical (O.2), the nitric oxide radical (NO.) and the lipid peroxyl radical (LOO.). Most of the superoxide radicals are formed in the mitochondrial and microsomal electron transport chain. The hydroxyl free radicals are very reactive species and rapidly attack the macromolecules in cells. The superoxide radical, lipid hydroperoxides, and nitric oxide are comparatively less reactive. A limited number of enzymes like xanthine-oxidase, tryptophan dioxygenase, and indole-amine dioxygenase produce the superoxide free radical directly. Further, nitric oxide free radical (NO) can react with superoxide radical to form a highly toxic peroxynitrite (ONOO). When peroxynitrite reacts with human body fluids and tissues, nitrotyrosines are generated, which have been detected in human brain and may be increased in neurodegenerative diseases.

14. Free radicals or Reactive oxygen species (ROS) causes several damaging effects by attacking the lipids, proteins, enzymes, carbohydrates, and DNA of cells and tissues. They induce undesirable oxidation, causes membrane damage, protein modification, DNA damage, and cell death induced by DNA fragmentation and lipid peroxidation. This oxidative damage associated with free radicals is believed to be involved in the pathophysiological role in aging of skin and also in several diseases like heart disease (atherosclerosis), cataract, cancer, diabetic retinopathy, chronic inflammatory diseases of the gastrointestinal tract, organ dysfunction, disseminated intravascular coagulation, chronic neurodegenerative diseases like parkinson’s diseases, multiple sclerosis, amyotrophic lateral sclerosis, spastic paraplegia, alzheimer’s diseases etc. Antioxidants are believed to slow down the formation of free radicals, protects the body by repairing the damage of cells and tissues.

17. ANTIOXIDANT PROPERTY OF NONI The Endogenous antioxidants system and Role of Noni: Our body has evolved with endogenous defense mechanisms to protect against free radical induced cell damage. Glutathione peroxidase, catalase, and Superoxide dismutases are three primary antioxidant enzymes in our body , which involved in direct elimination of free radicals or reactive oxygen species from our body. They require micronutrient such as selenium, iron, copper, zinc, and manganese as cofactors for their formation and optimum catalytic and effective antioxidant activity. Noni contain all the trace minerals that help for optimum catalytic activity of those three important antioxidant enzymes for an effective antioxidant defense mechanism.

18. Glutathione, ascorbic acid, alpha-tocopherol, beta-carotene, bilirubin, selenium, melatonin, uric acid etc., as a whole play a homoeostatic or protective role against ROS produced during normal cellular metabolism and after active oxidation insult. Noni contains many of the above phyto chemicals and vitamins in abundant quantity. Glutathione (GSH) is the most significant component which directly quenches Reactive Oxygen Species (ROS) such as lipid peroxides and plays major role in xenobiotic metabolism. Glutathione is a tripeptide made up of the amino acids gamma-glutamic acid, cysteine, and glycine. Noni contain all those glutathione making amino acids in abundant number.Thus Noni increases the body’s glutathione level. Noni stimulates more melatonin secretion from the pineal body. It also maintains ascorbate (vitamin C) and alpha-tocopherol (vitamin E), in their reduced form, which also exert an antioxidant effect by quenching free radicals.

20. The Exogenous antioxidants: Contribution from Noni: A number of other dietary antioxidants known as phytonutrients or phytochemicals that are being increasingly appreciated for their antioxidant activity. One example is flavonoids which are a group of polyphenolic compounds. They are responsible for the different brilliant colors such as blue, scarlet, and orange. Noni contain 150 above phytochemicals including all flavonoids. Flavonoids exhibit several biological effects such as antitumoural, anti-ischaemic, anti-allergic, anti-hepatotoxic, anti-ulcerative, and anti inflammatory activities. These are also known to inhibit the activities of several bad enzymes like lipoxygenase, cyclooxygenase, monooxygenase, xanthine oxidase, glutathione-S transferase, mitochondrial succino-oxidase, and protein kinases. Many of the biological activities of flavonoids are attributed to their antioxidant properties and free radical scavenging capabilities. Noni is rich with many flavonoids. Due to the inefficiency of our endogenous defense systems as well as highly exposure to environmental factors such as ,cigarette smoke, air pollutants, UV radiation, and also the existence of some physiopathological situations like inflammation, ischaemia/reperfusion, the ROS are produced in excess, and therefore increasing amounts of antioxidants present in Noni will be needed for diminishing the cumulative effect of oxidative damage over an individual’s life span.

22. OXIDATIVE STRESS IN THE NERVOUS SYSTEM The oxidative stress is a shift towards the pro-oxidant (free radicals) in the pro-oxidant/antioxidant balance system that can occur as a result of an increase in oxidative metabolism. Its increase at the cellular level can come as a consequence of several factors, including exposure to alcohol, cold, medications, trauma, infections, toxins, radiation, strenuous physical activity, and poor diet. Defense against all of these processes is dependent upon the adequacy of various antioxidants that are found abundantly in Noni. The nervous system – including the brain, spinal cord, and peripheral nerves – is rich in both unsaturated fatty acids and iron. The high lipid content of nervous tissue, coupled with its high aerobic metabolic activity, makes it particularly susceptible to oxidative damage.

23. There are several reasons why the brain and the nerves are especially vulnerable to oxidative stress. • Relative to its size, the brain experiences an increased rate of oxidative activity, which creates a significant number of free radicals. • The normal activity which various chemicals create to establish nerve conduction is a major producer of free radicals. The brain and nerve tissue contain relatively low level of antioxidants. • In addition, those brain regions that are rich in catecholamines are exceptionally vulnerable to free radical generation. The catecholamine adrenaline, noradrenalin, and dopamine can spontaneously break down (auto-oxidise) to free radicals, or can be metabolized to radicals by the endogenous enzymes such as MAO (monoamine oxidases). One such region of the brain is the substantia nigra (SN), where a connection has been established between antioxidant depletion (including GSH) and tissue degeneration.

24. A number of in vitro studies have shown that antioxidants – both endogenous and dietary supplements (Noni) – can protect nervous tissue from damage by oxidative stress. Vitamin E was found to prevent cell death (apoptosis) in rat neurons subjected to hypoxia followed by oxygen reperfusion. In the same study it was shown that vitamin E prevented neuronal damage from reactive nitrogen species. Both vitamin E and beta carotene were found to protect rat neurons against oxidative stress from exposure to ethanol. In an experimental model of diabetes-caused neurovascular dysfunction, beta-carotene was found to protect cells most effectively, followed by vitamin E and vitamin C. Most in vivoand clinical studies of the effects of lipid soluble antioxidant supplementation on neurological diseases have focused on vitamin E. A report in 1991 demonstrated that the rate at which Parkinson’s disease progressed to the point when the patient required treatment with levodopa was slowed by 2.5 years in patients given large doses of vitamin C and vitamin E and other essential antioxidants .

25. In a study, it was found that the risk for Parkinson’s disease was lower for subjects who had higher dietary intakes of antioxidants. In another study, it was found that patients suffering from Parkinson’s disease had consumed less of the antioxidants, beta-carotene and vitamin C than did non-sufferers of the disease, implying that dietary antioxidants found in Noni do play a protective role in this disease.

26. There is substantial evidence that oxidative stress is a causative or at least ancillary factor in the pathogenesis of major neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) as well as in cases of stroke, trauma, and seizures. • Decreased levels of antioxidant enzyme activity have been reported in patients with Parkinson’s disease. Evidence of increase in lipid peroxidation and oxidation of DNA and proteins has indeed been seen in the substantia nigra of patients affected with Parkinson’s disease. • Similar increases in markers of oxidative stress have also been seen in Alzheimer’s disease, and in both familial ALS (FALS) and sporadic ALS (SALS) patients.

27. Schizophrenia (SCZ) is also believed to have a component of free-radical overload. Lipid peroxides have been found elevated in their blood and increased pentane gas, a marker for lipid peroxidation, in the breath of schizophrenics as compared with normal volunteers and with patients having other psychiatric illness. The enzyme SOD was found increased, possibly as an adaptive response to free radical overload in the patients of SCZ. Studies of antioxidant treatment in schizophrenia have been very few. Glutathione peroxidase level are also found reduced in SCZ patients. Therefore a powerful antioxidants like Noni plays a vital role in schizophrenia patients.

28. CONCLUSION Neurodegenerative disorders remain an important source of morbidity and suffering for the humankind. The role of free-radical-mediated oxidative injury in acute insults to the nervous system including stroke or trauma, as well as in chronic neurodegenerative disorders, is being just recognized. As we know, oxygen is an essential molecule for survival of majority of living organisms. Oxidative stress is the harmful condition that occurs when there is an excess of free radicals and/or a decrease in antioxidant levels. There is evidence to suggest that increase in energy metabolism by aerobic pathways enhances the intracellular concentration of free oxygen radicals, which in turn enhance the rate of the autocatalytic process of lipid peroxidation, inducing damage to brain structures, especially when physiological defenses become insufficient or depleted. Antioxidants found in Noni combat oxidative stress by neutralising the excess free radicals.

29. The evidence to date for oxidative stress in PD, ALS, SCZ, AD and other neurodegenerative diseases is strongly persuasive. Clinical studies show that a number of events associated with Alzheimer’s diseases are capable of stimulating production of free radicals and depletion of antioxidant levels. Patients with Parkinson’s diseases also have reduced glutathione levels and free radical damage is found in the form of increased lipid peroxidation and oxidation of DNA bases. Tackling of the free radical involvement offers a novel therapeutic target in such diseases.

30. In the above Neuro Degenerative diseases when oxidative stress is eventually proven to be primary or secondary in the aetiologic progression, the therapeutic rewards of powerful antioxidants like Noni are likely to be substantial. The essential consideration is to provide a powerful antioxidants like Noni in those neurodegenerative diseases within the time frame of or prior to maximal tissue damage. Clearly, strategies should aim at limiting the free radicals production and oxidative stress, that may slow the progression of neurodegenerative diseases. Patients can replete their cellular and body stores antioxidants with the body’s most important antioxidants, glutathione and other antioxidants through Noni to maintain the antioxidant defense system that will help to prevent or delay the progression of free radical related damages.

31. Noni contains all the antioxidant vitamins such as Vitamin C, vitamin E, beta-carotene, and all antioxidant trace minerals, glutathione and lots of phytochemicals that may helps in preventive and therapeutic role in various chronic neurodegenerative diseases. Preclinical experimental studies have proven that Noni can reduce acute neurological disorders by preventing lipid peroxidation and diminishing free radical generation. In fact, they appear to be highly beneficial in experimental models.

32. CASES UNDER CLINICAL TRIAL Name: Sudhir Chandra Pradhan. Age & sex: 78 Male Address: Plot No 43,Laxmi Bihar, Sainik School, Bhubaneswar - 751005 Date: 10th July 2006 Diagnosis: • Alzheimer's diseases • Seizure • Metabolic encephalopathy

33. CLINICAL SIGNS AND SYMPTOMS