Transcript NONI IN NEURODEGENERATIVE DISEASES

NONI
IN
NEURODEGENERATIVE
DISEASES
Parkinson’s Disease
Alzheimer’s disease
Senile Dementia
Amyotrophic Lateral Sclerosis (ALS)
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 freeradical-mediated oxidative injury to the nervous system like strokeor
traumaand various chronic neurodegenerative disorders are
being recognized.
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.
ROLE OF INDIAN NONI IN CHRONIC NEURODEGENARATIVE
DISEASES
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 freeradical-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
SOME COMMON NEURO DEGENERATIVE DISEASES

Parkinson’s Disease

Alzheimer’s disease

Frontotemporal Dementia

Amyotrophic Lateral Sclerosis (ALS)
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.
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.
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
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
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.
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.
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.
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 gammaglutamic 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.
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, antihepatotoxic, 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.
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.
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.
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, betacarotene was found to protect cells most effectively, followed by vitamin E
and vitamin C. Most in vivo and 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 .
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.
• 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.
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.
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.
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.
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.
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
peroxidation
disorders
by
preventing
lipid
and
diminishing free radical generation. In fact, they appear to be highly
beneficial in experimental models.
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:
1.
Alzheimer's diseases
2.
Seizure
3.
Metabolic encephalopathy
CLINICAL SIGNS AND SYMPTOMS
BEFORE USING NONI
AFTER USING NONI- 78 DAYS
Drowsiness
No drowsiness
Unable to sit or walk (No paralytic
conditions)
Sitting on bed without any
support. Standing and walking
with little support
Memory impaired.
Trying to recognize his family
members.
Not responsive to any question
asking
Response to all question but
speech is not clear
B.P – 150/100 mm of Hg
BP – 130/90 mm of Hg
Serum Na – 118 mmol/l (30th June Serum Na – 126 mmol/I (Dt 18th
2006)
September 2006)
Disturbed sleep
Sound sleep
Hb % - 11g/dl
Palm and plantar reflection –
normal
Palm and plantar reflection –
normal
CT Scan of head – Cerebral
Atrophic condition
CT Scan has not been done
afterwards