This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
Herbal medicine is the natural system of medicine that has been practiced for more than 5000 years. Ayurvreda is a Sanskrit word and its meaning is 'science of life (or) practice of longevity'' this system of health care was conceived and developed by the rishis and natural scientist through centuries of observation, discussion and medication based on trial and error.
Herbs are the major components in all indigenous preparation of traditional medicine and common element in Ayurveda, homeopathic naturopathic and Native American Indian medicine. Herbal medicine emphasizes prevention of disease, rejuvenation of our body systems and it extends the life span and makes healthy life in balance and harmony.
From ancient time to the present people throughout the world had maintained a vast and initiate knowledge of native plants. The plant kingdom has provided innumerable sources of medicinal plants, first used in crude form as herbal teas, syrups, infusions, ointments, liniments and powders.
Herbal medicine, sometimes referred as herbalism (or) botanical medicine is the use of herbs for their therapeutic (or) medicinal value. An herb is a whole plant (or) plant part valued for its medicinal aromatic (or) acceptable qualities. Herbal plants contain variety of chemical substances that act upon the body.
Herbal medicine is the oldest form of health care known to mankind. Herbs have been used by all cultures throughout the history. It was an integral part of the development of modern civilization primitive man observed and appreciated the great diversity of plants available to him. The plant provided food, clothing shelter and medicine. Much of the medicinal use of plants seems to have been developed through observations of wild animals, and by trial and error. As the time went on each tribe added the medicinal power of herbs in their area to its knowledge base. They methodically collected information on herbs and developed well defined herbal pharmacopoeias.
The history of herbal medicines is as old as human civilization. The plants were used in the traditional system of medicine practiced in China, Egypt, and Greece long before the beginning of the Christian era.
Truly well in to the 20th century much of the pharmacopoeias of scientific medicine were derived from the herbal folklore of native peoples. Many drugs commonly used today are herbal origin. Indeed about 25 percent of the prescribed drugs dispended in the United States contain at least one active ingredient derived from plant material some are made from plant extracts; others are synthesized to mimic a natural plant compound.
The Indian health care science has inherited a large number of traditional practices, systems, medicines as part of its holistic health care scenario, some of them more than 3000 years old. The earliest mention of the medicinal use of plants is to be found in the Rigveda which dates back as early as 3500 BC. It is Ayurveda, the Adharvanaveda, is considered to be the ancient medical science of India.
Natural product is a single chemical containing compound that occurs naturally. This term is typically used to refer to an organic compound of limited distribution in nature (often called secondary metabolites). Natural products have been a major source of drugs for centuries. With more than 25% of the pharmaceuticals in daily use of todays are derived from natural products, so therefore interest in natural products research remains strong.
This is belonging to several factors, including unmet therapeutic needs that compel new drug discovery, the remarkable diversity of both chemical structures and biological activities of naturally occurring secondary metabolites, the utility of bio-active natural products as biochemical and chemical probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constitutes, advances in solving the demand for bulk supply of complex Natural products, and the success of herbal remedies in the global market place.
With the advancement of the chemistry and western medicine the active substances of many species have been isolated and utilized. According to WHO estimation 80% of world population presently uses the herbal medicine for specific primary health care; about 25% of the prescription drugs dispended to us contain at least one active ingredient of plant origin. (Forsten GE, 2002)
Laboratorial and clinical investigation on herbal preparations and other therapies shows that they have a various range of potential results for treating infectious diseases, diabetes and promoting health. Mechanisms underlying these effects may comprise free radical scavenging, brain neurotransmitter modulation and hormonal effects.
The present specified direction is to replace the crude plants with the pure active principles has been started with the investigating work in 18th century by isolating organic acids from plants. The active constituents from plants have been curing off the elements with less threat of adverse reactions. The synthetic preparations of some drugs are either unknown (or) economically impractical. So for these reasons scientists are continuing to search for and test little known plants and conserve those medicinal properties which have become critical in fight against diseases.
Extremely large opportunities exist for multi disciplinary research that joins the forces of pharmacognosy and natural products chemistry, molecular and cellular biology, medicinal and analytical chemistry, biochemistry, pharmacology and pharmaceutics to exploit the vast diversity of chemical structures and biological activities of Natural products.
A large portion of the Indian population even today depends on the Indian system of medicine, the well known treatises in Ayurveda are charaka, sanhita, sushrutha samhita, vakbahta samhita,ratnavati etc; and they in detail the curating properties of herbs, minerals etc.
Ayurveda - ancient science of life is believed to be prevalent for last 5000 years in India. It is one of the oldest systems of medicine in the world. Ayurveda is based on hypothesis that everything in the universe is composed of five basic elements viz. space, air, energy, liquid and solid. They exist in the human body in combined forms like vata (space &air); pita and kapha together are called tridosha (three pillars of life).
Tridosha found in human body is seven forms called saptodhato viz Rasa (lymph), rakta (blood), meda (adipose tissue), mamsa (flesh), majja (neurine tissue), shukra (reproductive tissue) and asthi (bones). These tissues are subjected to wear and tear so that mala (excretory material) is formed from them. When tridosha, saptadathu and mala are in balance with each other, it is called healthy condition (roga). It is hypothesized that the five characters of the medical herbs viz. rasa, guna, virya, vipak, and prabha can be applied to treat various pathological conditions.
Ayurvedic pharmacy proposes many dosage forms like swaras, kalka; kwath, hima, arishta, asava, chuirna, avalesh, chrita, sandhana, kalpas, bhasmas etc; asavas and avishtas are prepared from water decoctions of plants by fermentation techniques.
Organizations like world health organization (WHO) and United Nations children's educational fund (UNICEF) are very much interested in plants to be used for the treatment various diseases of children.
Plants and plant based drug are relatively less toxic and have acceptable side effects. It is therefore essential to bring the use of the remedies in to an existing frame work (or) rational scientific use of medic
Oxidative stress is to be involved as one of the primary factors that contribute to the development of neurodegenerative diseases like, Alzheimer's, Parkinsonism and neurological conditions like brain damage, epileptic seizures, stroke, neurotrauma, hypoxia etc;
Morphological, biochemical and molecular studies which are undertaken in the recent years both in experimental animals and in man have shown that oxidative stress plays a fundamental role in the development of degenerative changes in cells and tissues of our body. The highest degree of oxidative damage usually occurs in organs like brain, heart and skeletal muscles, since these organs are composed primarily of post mitotic cells. The central nervous system shows increased susceptibility to oxidative stress because of its high oxygen consumption rate (20% of the total oxygen inhaled by the body)that accounts for the increase in generation of oxygen free radicals and reactive oxygen substances like superoxide radical (O2), single oxygen (O2), H2O2 and hydroxyl radical (OH).
During this stage all the cells and tissues of our body are also equipped with anti oxidative enzymes like super oxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GRD) and substances like reduced glutathione (GSH). They dispose the free radicals as and when they are generated thereby protecting the cells and tissues from the oxidative harms. Generally the balance is maintained between the oxidative attack of the free radicals and the anti oxidative defense system existing in the cells and tissues of our body. (Srinivasan V, 2002).
Several series of stages disturb this balance by increasing the formation of free radicals in comparitatively to the available oxidants (thus, oxidative stress),example of free radical formation, immune cell activation, inflammation ischemia, infection, cancer and so on, free radicals and the effect of these toxic molecules on cell function (which can result in cell death) known as oxidative stress. These free radicals are highly reactive, unstable molecules thus unpaired electron in their outer most shells. They react with (oxidize) various cellular components and free radicals lead to DNA damage, mitochondrial dysfunction, cell membrane damage ,and eventually cell death (Apoptosis-which is called as cell death). (Haiwell B, 2001)
Brain has a low level of anti-oxidative defense system. The concentration of various anti-oxidant enzymes like SOD, GPX, GRD, catalase, is low in the brain. The glutathione (GSH) concentration is also very much reduced in the brain when compared to other organs in the body. In addition to these factors brain has high iron and ascorbate content in the certain region, which provides favorable conditions for generation of oxygen free radicals.
Brain is also enriched with polyunsaturated fatty acid (PUFA) that renders them susceptible to oxidative attack. The inter play of all these factors that contribute to enhance oxidative stress is out lined
PROOXIDANT FACTORS IN BRAIN
High oxygen utility
Enrichment with PUFA
High iron and ascorbate content
PREOXIDANT FACTORS IN BRAIN
Low glutathione peroxidase
Melatonin (declines with age)
Increased free radical generation
(O2-, H2O2 OH LOO- ONOO-
Increased oxidative stress
The increased level of oxidative stress in the brain is the major contributory factor for the development of neurodegenerative diseases like Alzheimer's disease hypoxia and Parkinsonism in aged individuals.
HYPOXIA INDUCED NEURODEGENERATION:
Cerebral hypoxia relates to condition in which there is a decrease of oxygen supply to the brain even though there is adequate blood flow, symptoms of mild cerebral hypoxia include inattentiveness, poor judgment, memory loss, decrease in motor co-ordination. Brain cells are extremely sensitive to oxygen lacking and can begin to die within five minutes after oxygen supply has been cut off, when hypoxia lasts for longer periods of time it results in coma, seizures and even brain death. (Ninds cerebral hypoxia)
Estimation of learning and memory in hypoxic condition is to say the drugs activity in the neuroprotective conditions. Hypoxia can be induced either by decreasing the oxygen level or by administration of the chemicals decreasing the oxygen level in the biological system leads to oxidative stress in the cells, and may lead to cell mediated dysfunction and then apoptosis. The oxidative stress hypothesis is appealing for AD and other neurodegenerative disorders, since neurons are post mitotic cells and gradual cumulative oxidative damage over time could account for the late life on set and the slowly progressive nature of the disorders. (Coyle JT et al., 1983).Inducement of synthesis of NO generation may precipitate hypoxia due to its more affinity to hemoglobin. sodium nitrite oxidizes, oxy hemoglobin to methemoglobin and also yielding nitrites (NO2) and nitrates (NO3). Nitric oxide binds slowly and reversibly to hemoglobin that eventually auto releases by a first order reaction to Hbfe2+No Further NO2 oxidizes oxy hemoglobin by an auto catalytic reaction. And finally NO2 binds reversibly to methemoglobin to yield a mixture of complexes. (Feelisch M et al., 1987)
All this reaction put the biological system in to oxidative stress and resulting apoptosis this statement supports our finding with sodium nitrite administration in rats. Early cessation of electrical activity (firing) caused by K+ conductance mediated neuronal hyper polarization and disappreance of excitatory synaptic potentials can be seen as a protective mechanism that prevents the cellular damage resulting from severe mismatch between energy needs and supplies. These changes are triggered by such hypoxia induced signals as a rise in cytoplasmic free calcium fall in adenosine triphosphate (ATP)and extra cellular accumulation of adenosine (produced by ATP break down) upon reoxygenation the suppression of neuronal synaptic activity is quit reversible as long as hypoxic nerve cells have an adequate supply of glucose. But if sufficient ATP cannot be obtained by anaerobic glycolysis to maintain essential Na+k+ pump activity and protein synthesis, long term cell function and survival are compromised thus when both oxygen and glucose are deficient as in strokes the cellular protective mechanism cannot prevent the lethal effects of excessive Ca2+ influx. (Kresmir K, 1994).
Hypoxia and ischemia results over accumulation of glutamate and active the post synaptic glutamate receptors which initiate the detrimental biochemical cascade in the post synaptic neuron. These processes ultimately lead to DNA degradation, Lipid peroxidation and neuronal cell death. (Lipton S et al., 1994)
Hypoxia mainly disturbs the Ca2+ haemostasis, brain metabolism
(Figure 1 and 2).
Intracellular calcium and loss of homeostasis
Increased intracellular fluid of Ca2+ results from failure of energy dependent Ca2+-Mg2+ ATP ase pump and is also related to increase membrane permeability.
Figure: 1. Normal Neuron
Figure: 2 Intracellular calcium and loss of Hemostatis.
Figure: 3. Mitochondrial membrane disruptions leading to irreversible dysfunction and marked ATP depletion. (Radasideh M et al., 2002)
Sustained rise in intracellular Ca2+. This event is considered the initial step of irreversible injury. Sustained increased intracellular fluid of Ca2+ leads to action of intracellular self destructive lysosomal enzymes and that destroy the mitochondrial membrane, cellular membrane and other organelle membranes.
Increase in mitochondrial Ca2+ content and ionized Ca2+ concentration are observed during and after ischemic and hypoxic exposure and have traditionally been considered to impair mitochondrial function. (Silverman HS,1993).
The excessive accumulation of Ca2+ in neuronal and others tissues may represents the final common path way for cell death arising from hypoxia-ischemia because of the distribution of intracellular calcium haemostatis. (Stein DT et al., 1988)
When the pathological influence result in an increased permeability of the cellular membrane and the Ca2+ level in cytosol rises these ions can enter the cells playing a particular role in their damage by activating enzymes such as lipases proteases and endonucleases, they may lead to neurotic cell death.
GLUTAMATE INDUCED NEURODEGENERATION:
Glutamate is the major excitatory neurotransmitter in the mammalian brain. About 70% of all synapses in the central nervous system utilize glutamate as a transmitter. Glutamate is essential for various physiological processes such as learning and memory perception and executions of motor acts. However enhanced level glutamate as observed in several CNS disorder is associated with neurodegeneration
Glutamate is widely and fairly distributed in the CNS and it's concentration in the CNS is much higher than the other tissues. It has very important metabolic rate the metabolic neurotransmitter pool is linked by transmitter enzymes that catalase the inter conversion of glutamate and alpha-oxoglutarate,glutamate in the CNS comes mainly from glucose via the tricarboxylic acid cycle or glutamine which is synthesized by glial cells and taken up by the neurons very little come from periphery. Glutamate is stored in the synaptic vesicles and released by calcium dependant exocytosis. The action of glutamate is terminated by carrier mediated reuptake in the nerve terminals and neighboring astrocytes. (Yuone HO)
Four main subtypes of glutamate receptors have been distinguished namely N-methyl-D-aspartate (NMDA), ¡-amino -3-hydroxy -5-methyl-4-isoxazole propionate (AMPA), kainite and metabotropic, the first three are ionotropic receptors and metabotropic receptors is a D-protein coupled receptors. Binding studies show that glutamate receptors are abundant in cortex, basal ganglia and in sensory pathways.
Calcium overload is the essential factor in the exitotoxicity.the mechanisms by which this occurs and leads to cell death are as follows (Figure 4).
Glutamate activates NMDA, AMPA (¡-amino-3-OH-5-methyl.4-isoxazole propionate) and metabrotopic receptors (site 12 and 3) activation of AMPA receptors depolarize the cell, which unblocks the NMDA - channel permitting Ca2+ entry depolarization also opens voltage activated calcium channels (site 4) releasing more glutamate. Metabotropic receptors cause the release of intra cellular Ca2+ from the endoplasmic reticulum. Sodium entry contributes to Ca2+ entry by stimulating Ca 2+ / Na+ exchange (site 5). Depolarization inhibits or reverses glutamate uptake (site 6). And thus increases the extracellular glutamate concentration.
The mechanisms that normally operate to counteract the rise (Ca2+) include the Ca2+ efflux pump (site 7) and indirectly the Na+ pump.
The mitochondrial and endoplasmic reticulum act as capacious sinks for Ca2+ and normally keep [Ca2+] under control. Loading of mitochondrial stores beyond a certain point, however disrupts mitochondrial function reducing ATP synthesis, thus reducing the energy available the membrane pups and for Ca2+ accumulation by the endoplasmic reticulum, formation of reactive oxygen species (ROS) is also enhanced. They represent the danger point at which positive feedback exaggerates the process.
Figure: 4 Mechanism of Exitotoxicity
Raised (Ca2+) affects many processes the relevant to neurotoxicity being increased glutamate release activation of proteases (calpins) and lipases causing membrane damage.
Activation of nitric oxide synthetase (NOS) while low concentrations of NO are neuroprotective, high concentration generate peroxynitrite and hydroxyl free radicals, which damage many important biomolecules including membrane lipids proteins and DNA .Increased arachidonic acid release which increases the free radical production and also inhibits glutamate uptake. (Rang HP, Dale MM, 2005).
A number of pharmacological data indicate the involvement of glutamate in pathophysiology of anxiety and depression several neurotransmitter mediate the different components of anxiety including excitatory amino acids such as glutamate, inhibitory amino acids such as gamma-amino butyric acid (GABA) and monoaminergic neurotransmitters such as catecholamine's and iodole amines, different aspects of the anxiety response are mediated by various neurotransmitters in anatomically distinct areas. Thus imprinting of emotionally traumatic memories is mediated. In part by non epinephrine action through the beta adrenergic receptors in the amygdale. The development of conditioned fear is mediated by dopamine-1 receptors in the amygdale leading to facilitation of declarative memory associates through the hippocampus. (Ninan PT,1999)
Mematine is a non competitive low to moderate affinity NMDA receptor antagonist with an apparent dual mechanism of action. At the receptor level it displays rapid binding properties and a pronounced voltage dependency that modulate the glutaminergic neurotransmission system. In the state of reduced glutamate release in mean time produces improved neurotransmission and activation of neurons; however when glutamate release is excessive inhibits the excitatory action of glutamate by antagonizing NMDA receptors. The drug thus blocks NMDA receptors from excessive glutaminergic stimulation and prevents an increase in calcium influx, it subsequently result in decreased cell death and alleviates symptoms of AD. The affinity of meantime for cerebellar tissue is thought to be higher than that for frontal lobe brain tissue. (Yuone HO, 2004)
Hypoxia is defined as reduced availability of oxygen to the tissues. The term anoxia refers to absence of oxygen. In olden days the term anoxia was in use. Since there is no possibility for total absence of oxygen in living conditions, the use of this term is abandoned
CLASSIFICATION AND CAUSES OF HYPOXIA: (sembulingam et al., 2006)
Four important factors which leads to hypoxia are
Oxygen carrying capacity of blood
Rate of blood flow
Utilization of oxygen by the cells
Oxygen tension in arterial blood
Hypoxia can be classified as
Hypoxic hypoxia means the decreased oxygen content in the blood, it is also called arterial hypoxia.
CAUSES FOR HYPOXIC HYPOXIA:
Respiratory disorders associated with decreased pulmonary ventilation which does not allow intake of enough oxygen.
Respiratory disorders associated with inadequate oxygenation in lungs which does not allow diffusion of enough oxygen.
Cardiac disorders in which enough blood is not pumped to transport oxygen.
Low oxygen tension in inspired air reduces in the following conditions:
While breathing air in closed space
While breathing gas mixture containing low partial pressure of oxygen.
Pulmonary ventilation decreases in the following condition:
Obstruction of respiratory passage in asthma.
Nervous and mechanical hindrance to respiratory movements as in poliomyelitis
Depression of respiratory centers as in brain tumors
Oxygenation of blood in lungs reduces by the following conditions:
Impaired alveolar diffusion as in emphysema.
Presence of nonfunctioning alveoli as in fibrosis.
Filling of alveoli with fluid as in pulmonary edema, pneumonia, pulmonary hemorrhage.
Collapse of lungs as in bronchiolar obstruction.
Lack of surfactant.
Abnormal pleural cavity such as pneumothorax, hydrothorax, hemothorax, and pyrothorax.
Venous arterial shunts were deoxygenated blood is mixed with oxygenated blood.
Congestive heart failure.
Inability of the blood to carry enough amount of oxygen is known as anemic hypoxia the oxygen availability is normal. But the blood is not able to take up sufficient amount of oxygen due to anemic condition.
CAUSES FOR ANEMIC HYPOXIA:
Decreased number of RBCs
Decreased hemoglobin content in blood
Formation of altered hemoglobin
Combination of hemoglobin with gasses other than oxygen and carbon dioxide.
Decreased RBC due to conditions like bone marrow diseases. hemorrhage
Decreased hemoglobin content is due to the conditions which decrease the number of RBC or change in the structure of shape and size of RBC can decrease hemoglobin content in blood.
Formation of altered hemoglobin is due to poison with chlorates, nitrates, ferricyanides, etc causes oxidation of iron in to ferric form and hemoglobin is known as methemoglobin.
When hemoglobin combines with carbon monoxide hydrogen sulfide or nitrous oxide, It losses the capacity to transport oxygen.
Hypoxia due to decreased velocity of blood flow is known as stagnant hypoxia.
CAUSES OF STAGNANT HYPOXIA:
Stagnant hypoxia occurs mainly due to reduction in rate of blood flow. The velocity of blood decreases by the following conditions.
Congestive cardiac failure
The inability of tissue to utilize oxygen is called histotoxic hypoxia.
CAUSES FOR HISTOTOXIC HYPOXIA:
Histotoxic hypoxia occurs due to cyanide or sulfide poisioning these poisonous substances destroy the cellular oxidative enzymes and there is complete paralysis of cytochrome oxidase system.
EFFECTS OF HYPOXIA: (Laurence et al., 2006)
Hypoxias stimulate juxtaglomerular apparatus of kidneys and increase the secretion of erythropoietin. Erythropoietin in turn stimulates the redbone marrow, so the RBC count increases with increase of reticulocyte count, thus the oxygen carrying capacity of blood is improved by increase in RBC count and hemoglobin content.
ON CARDIOVASCULAR SYSTEM:
Initially, due to the reflex stimulation of cardiac and vasomotor centers, there is increase in heart rate, force of contraction of heart, cardiac out put and blood pressure later and there is reduction in the rate and force of contraction of heart. Cardiac output and blood pressure also decreased.
Initially respiration rate is increased due to the reflex through chemoreceptors large amount of carbon dioxide is washed out leading to alkalemia. Later the respiration tends to be shallow and periodic finally the rate and force of breathing are reduced to great extent due to the failure of respiratory centers
ON DIGESTYIVE SYSTEM:
Hypoxia is associated with loss of appetite, nausea and vomiting. Mouth becomes dry and there is a feeling of thirst.
5. ON KIDNEYS:
Hypoxia causes increased secretion of erythropoietin from the juxtaglomerular apparatus of kidney, and alkaline urine is excreted.
6. ON CENTRAL NERVOUS SYSTEM:
Depression of apathetic with general loss of self control. The person is talkative quarrelsome ill tempered and rude there is disorientation and loss of discriminative ability and loss of power of judgment, memory is impaired. Weakness lack of coordination and fatigue of muscle, loss of consciousness coma and death will occur.
ROLE OF NITRIC OXIDE IN BRAIN HYPOXIA:
The brain is particularly susceptible to interferences with its blood supply. thus, in the absence of blood flow, and therefore of oxygen, the energy reserves of the brain are capable of sustaining ATP levels for about 1 min. Cerebral metabolism depends upon continuous supply of glucose and oxygen. When asphyxia is prolonged, cerebral blood flow (CBF) decreases because of the fall in cardiac output. Nitric oxide has both neurotoxic and neuroprotective effects. (Juan PB et al., 1999)
NITRIC OXIDE BIOSYNTHESIS IN BRAIN: (Vincent SR, 1994, Bredt DS et al., 1990, Knowels RG et al., 1994)
NO is the physiological messenger in the central nervous system and is synthesized by the NO synthetase (NOS) -catalyzed reaction. Activation of NOS forms NO and L-citrulline from L-arginine, thus participating in the transduction pathway leading to elevations in intracellular cyclic GMP levels. This free radical involved in important functions such as the regulation of CBF (or) memory, thus activation of the NOS within the endothelial cells produce NO, which diffuses in to the neighboring smooth muscles and activates guanylate cyclase, the increase in cyclic GMP causes smooth muscle relaxation and thus vasodilation, in the brain. Cerebellum is important site for NO production after activation of the NOS enzyme. Three forms of NOS have been found in the brain cells.
Neurons produce NO mainly by Ca2+-dependent activation neuronal NOS which is constitutively expressed in these cells.
Glialcells (astrocytes, microglia, and oligodendrocytes) synthesize NO mainly after calcium-independent inducible NOS expression by treatment with the endotoxin lipolysaccharide.
Endothelial cells produce NO by the constitutive Ca2+- dependent activity of endothelial NOS. Astrocytes are known to produce NO via the constitutive n NOS activity and both endothelial cells and neurons express iNOS after lipopolysaccharide treatment.
Under certain pathological condition, n NOS activation might be exacerbated and the excess NO thus formed becomes neurotoxic and may play a role in neurodegeneration, the mechanism is to be mediated by the hyperactivation of glutamate receptors,especially the N- methyl-D-aspartate (NMDA) subtype in the post synaptic neuron which leads to increased intracellular free Ca2+-subsequent n NOS activation and possibly, mitochondrial dysfunction and cell death, thus excess NO formation with in the brain leads to neuronal death involves energy depletion, lipid and protein peroxidarion, protein nitrosylation and DNA damage. (Dawson VL et al., 1991, Dawson VL et al., 1993, Dawson VL et al., 19960
Figure: 5 Neuro Protective Versus Neurotoxtic effects of nitric oxide in Hypoxia
Nitric oxide biosynthesis is increased by hypoxia. NO has been selectively detected in certain brain areas such as the cortex, hippocampus, hypothalamus, amygdale and substantia nigra during hypoxia. Brain endothelial cells have also been shown to increase NO production in hypoxia. (Kuppusamy P et al., 1995, Olesen SP et al., 19970
Figure: 6 Neurotoxicity of nitric oxide during hypoxia
Decreased oxygen availability within the neuron during an hypoxia may reduce the mitochondrial ATP production. Transient ATP depletion prevents the Ca2+- pumping from the cytostol into organelle, such as the endoplasmic reticulum. Therefore increases in cystolic Ca2+- activate the constititutive Ca2+- dependent n NOS. however n NOS activity depends on O2 avalibility. Thus during reoxygenation the O2 concentration increases sharply and n NOS fully activated in addition, rapid O2 availability may exceed the mitochondrial capacity to reduce O2 to H2O and hence super oxide anion (O2) production may be enhanced. If this is the case O2 avidly reacts with NO to form peroxynitrite (ONOO-) which is well known irreversible inhibitor of mitochondrial function and a pro-oxidant compound that damages lipids, proteins, and DNA, leading to neuronal cell death. (Cazevieille C et al., 1993, Beckman JS, 1991, Forman LJ et al., 1998)
Alzheimer's disease: (adear, 2008)
Alzheimer's disease is an irreversible progressive brain disease that slowly destroys memory and thinking skills and eventually, the ability to carry out simplest tasks of daily living. In most people with Alzheimer's disease, symptoms first appear after age 60.
Alzheimer's disease is the most common cause of dementia among older people, but it is not a normal part of aging. Dementia refers to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease starts in a region of the brain that affects recent memory, and then gradually spreads to the other parts of the brain. Although treatment can slow the progression of Alzheimer's disease, currently there is no cure for this devastating disease.
Epidemiology and prevalence:
In 1996, Alzheimer's disease was clinically diagnosed in approximately 10 million people in the India; this figure is expected to triple in the next 50 years. Women are more affected than men at a ratio of almost 2:1, partly because of the larger population of women who are older than 70 years; however, the prevalence is still higher in women even after statistical correction for longevity. Age is another risk factor. At the age of 60 years, the risk of developing Alzheimer's disease is estimated to be 1%, doubling every 5 years to reach 40% to 60% by the age 85. (Johns Hopkins, 2007). Alzheimer's disease also demonstrated a definite association in men.
The classic neuropathologic findings in Alzheimer's disease include amyloid plaques, neurofibrillary tangles, and synaptic and neuronal cell death. Granulovacuolar degeneration in the hippocampus and amyloid deposition in the blood vessels might also be seen on tissue examination.
Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of Î²-amyloid protein (AÎ²). AÎ² is a 39 to 42 amino acid peptide that is formed by the proteolytic cleavage of Î²-amyloid precursor protein (APP) and is found in extracellular deposits throughout the CNS. AÎ² is believed to interfere with neuronal activity because of its stimulatory effect on production of free radicals, resulting in oxidative stress and neuronal cell death.
Neurofibrillary tangles are paired helical filaments composed of tau protein, which in normal cells is essential for axonal growth and development. However, when hyperphosphorylated, the tau protein forms tangles that are deposited within neurons located in the hippocampus and medial temporal lobe, the parietotemporal region, and the frontal association cortices, leading to cell death.
Neuron and Synapse Loss
Areas of neuronal cell death and synapse loss are found throughout a distribution pattern similar to that of the neurofibrillary tangles, but they greatly affect neurotransmitter pathways. The death of cholinergic neurons in the basalis nucleus of Meynert leads to a deficit in acetylcholine (Ach), a major transmitter believed to be involved with memory. In addition, loss of serotoninergic neurons in the median raphe and adrenergic neurons in the locus ceruleus lead to deficits in serotonin and nor epinephrine, respectively. (Cummings JL et al., 1998)
Figure -7 Alzheimer's brain cells
1. Cholinesterase (KOH-luh-NES-ter-ays) inhibitors:
Prevent the breakdown of acetylcholine (a-SEA-til-KOH-lean), a chemical messenger important for learning and memory. This supports communication among nerve cells by keeping acetylcholine levels high.
Delay worsening of symptoms for 6 to 12 months, on average, for about half the people who take them.
Three cholinesterase inhibitors are commonly prescribed:
Donepezil (Aricept), approved to treat all stages of Alzheimer's disease.
Rivastigmine (Exelon), approved to treat mild to moderate Alzheimer's.
Galantamine (Razadyne), approved to treat mild to moderate Alzheimer's.
Tacrine (Cognex) was the first cholinesterase inhibitor approved. Doctors rarely prescribe it today because it's associated with more serious side effects than the other three drugs in this class.
2. Memantine (Namenda):
Regulates the activity of glutamate, a different messenger chemical involved in learning and memory.
Is approved to treat moderate to severe Alzheimer's disease.
Delays worsening of symptoms for some people temporarily. Many experts consider its benefits similar to those of cholinesterase inhibitors.
Doctors sometimes prescribe vitamin E to treat cognitive Alzheimer's symptoms. Vitamin E is an antioxidant, a substance that may protect brain cells and other body tissues from certain kinds of chemical wear and tear. Its use in Alzheimer's disease is based chiefly on a 1997 study showing that high doses delayed loss of ability to carry out daily activities and placement in residential care for several months. That study was conducted by the Alzheimer's disease Cooperative Study (ADCS), the clinical research consortium of the National Institute on Aging (NIA). Since the ADCS study was carried out, scientists have found evidence in other studies that high-dose vitamin E may slightly increase the risk of death, especially for those with coronary artery disease.
No one should take vitamin E to treat Alzheimer's disease except under the supervision of a physician. Vitamin E - especially at the high doses used in the ADCS study - can negatively interact with other medications, including those prescribed to keep blood from clotting or to lower cholesterol. (ADEAR, 2008)
Nausea, vomiting, loss of appetite and increased frequency of bowel movements.
Mild to moderate
Nausea, vomiting, loss of appetite and increased frequency of bowel movements.
Moderate to severe
Mild to moderate
Nausea, vomiting, loss of appetite and increased frequency of bowel movements.
Mild to moderate
Possible liver damage, nausea, and vomiting.
Can interact with medications prescribed to lower cholesterol or prevent blood clots; & increase risk of death.
Treatments for behavioral and psychiatric symptoms
In addition to affecting memory and other cognitive skills, Alzheimer's disease often affects the way people feel and act. Many people with Alzheimer's and their families find these symptoms the most challenging and distressing affects of the disease.
Common symptoms at different stages of Alzheimer's disease include:
Anxiety and depression
Anger or irritability
General emotional distress
Physical or verbal outbursts
Restlessness, pacing, shredding paper or tissues
Hallucinations (seeing, hearing or feeling things that are not really there)
Delusions (firmly held belief in things that are not true)
Folklore of herbs to heal Alzheimer's disease:
Lycorus radiata (shisuan)
Macleaya cordata (boluohui
Coptis chinenses (huanglian)
Securinega suffruticosa (yiyiqiu)
Ginkgo (Ginkgo biloba)
Gotu Kola (Centella asiatica)
Lemon Balm (Melissa officinalis)
Rosemary (Rosmarinus officinalis)
Parkinson's disease (PD) is a neurodegenerative disorder leads to movement disorders. The disease is characterized by muscle rigidity, tremor and a slowing of physical movement (bradykinesia) . Recent studies suggest that free radicals also have a key role in PD, as they can induce lipid peroxidation leading to neuronal death Characterized by loss of dopaminergic neurons in substantial nigra. The marker of lipid peroxidation, thiobarbituric acid reactive substance (TBARS) is increased in the brain of Parkinsonian patients.These may be due to the factors including reduced
Levels of antioxidants: GSH and GPx that may lead PD patients more vulnerable to oxidative stress. (Antonio. R. damasio et al., 1971).
Epidemiology and prevalence:
Parkinson's disease is the second common neurodegenerative disease after Alzheimer's disease. Worldwide estimation of dementia prevalence increases from 24 million of today to 81million in 2040. In India nearly about 23% people are suffering with this disease. Women are more prone to this disease than men.
In idiopathic Parkinsonism (paralysis agitans, Parkinson's disease, PD), there is depigmentation and relentless, progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). These neurons make efferent connections with neostriatum (putamen plus caudate nucleus) where they make contact with two types of neostriatal neurons:
1) Those bearing excitatory D1 receptors: These relay impulses via a direct excitatory pathway (medial globus pallidus-thalamus) to the cerebral motor cortex to
enhance stimulation by it of the spinal motor neurons.
2) Those bearing inhibitory D2 receptors: They relay impulses via an indirect inhibitory pathway (lateral globus pallidus- subthalmic nucleus-medial globus pallidus) to the same cerebral cortex to decrease stimulation by it of the spinal motor neurons the excitatory segments of these relay systems are glutamatergic whereas the inhibitory segments are GABAergic.
In healthy persons, the flow of impulses over the direct pathway predominates as the dopamine released in the neostriatum enhances the activity of the concerned neurons. In PD, dopamine deficiency has the opposite effect (dominance of the indirect pathway; as a result, the stimulation by the cerebral motor cortex of the spinal motor neurons markedly decreases. This accounts for the signs and symptoms of Parkinsonism.
The dopamine agonist bromocriptine which is taken by and acts on the neostriatum helps to correct this latter situation and relieves many but not all of the signs and symptoms. There are two candidate neurons / receptors for that phenomenon. One is the cholinergic type through which the inter-neurons within the basal ganglia operate.
The clinical features of PD can be explained by a combination of:
1) Increased activity of GABAergic neurons
2) Cholinergic preponderance
3) Dopamine deficiency. (Aarsland D et al., 1999).
Figure -8 Parkinson's brain
Current synthetic drugs for treatment of PD:
Trihexyphenidyl (Artane), the first synthetic preparation for Parkinsonism, remain the best.
Ethopropazine (Parsidol, Parsitan)
Azilect (rasagiline) that blocks the breakdown of dopamine
Folklore of herbs used to treat PD
St John's Wort
Vicia fava beans. (Manyam BV et al., 2004).
Coumarins and polyphenols in neuroprotection
It is proved by many researchers that plants with coumarin derivatives and polyphenols have the neuroprotective activity. The plant which I had selected (Aegle marmelos) also have the both coumarin and polyphenolic derivatives. So the neuroprotective activity of Aegle marmelos was not proved by anybody, so I have selected this topic for my project purpose.
Some of the plants with polyphenols and coumarin derivatives which are proved for their neuroprotective activity are:
Thuja orientalis leaves have the neuroprotective activity because of the presence of various coumarin derievatives. (Manyam BV et al., 2004).
Achyrocline satureioides (Lam) D.C. have the cytoprotection activity due to the presence of both Coumarins and polyphenols. (M.F. Arredondo et al., 2004).
Cassiae semen, a seed of Cassia obtusifolia have the neuroptotective activity due to the presence of various coumarin derievatives. (Mi Sun Ju et al., 2010).
Ageratum conyzoids have the neuroprotective activity because of the presence of various coumarin derievatives and flavanoids.
Green tea contains various polyphenols acting as neuroprotectives.( Tianhong Pan et al., (2003).