NEURODEGENERATIVE DISEASES- A REVIEW

About Authors:
Charu Pundir¹, Prof.Veermaram², Maroof Ali³, Abhishek Joshi⁴
¹B.Pharm, S.B.S.P.G.I, Dehradun, Presently studying M.Pharm. Pharmacology & toxicology at KLE University’s college of pharmacy, Belgaum, Karnataka
^2,H.O.D, Dept. of Pharmaceutical Sciences, S.B.S.P.G.I, Dehradun
³B.Pharm, S.B.S.P.G.I, Dehradun
⁴M.Pharm, Pharmacology, Kumaon University
pundir.charu1313@gmail.com

Absract:
Neuro degenerative disease is the umbrella term for the gradual loss of brain parts, including death of neurons. This may lead to Parkinson- a gait disorder, Alzheimer, which is a common form of dementia and occurs with progressive increase in age. Genetic mutations, Protein misfolding, Oxidative stress, Excitotoxicity, Infectious Organism are the basic cause behind neuro degeneration. This can be estimated through Verticulography, CAT SCAN, MRI, Pneumoencephalography and Cerebral angiography. AD is the accumulation of β- amyloid plaques and formation of neurofibrillary tangles related to hyperphosphorylation of tau proteins. Treatment therapy includes medications, surgery, ayurveda, physiotherapy, yoga and stem cell therapy.

REFERENCE ID: PHARMATUTOR-ART-1929

1. Introduction
The Forebrain is responsible for a variety of functions receiving and processing sensory information, thinking, producing and understanding language and controlling motor functions. Diencephalon and the Telencephalon are the major divisions of it. Adult brain consists of four parts: Brain stem, cerebellum, diencephalon and cerebrum. Cranium and the Cranial meninges surrounds and protect the brain. Blood flows mainly via the internal carotid and vertebral arteries; internal jugular veins return blood from the head to the heart. Various lobes like Frontal, Parietal, Temporal and Occipital are involved with decision making, problem solving, vision, recognition, memory, speech and sensory processes. Perception of pain and pleasure, control of movements and regulation of body functions such as breathing are regulated by Nervous system. It is divided into Central nervous system, consisting brain and spinal cord.^[25] Neurons works electrically, chemically and by inhibitory and excitatory mechanisms. Nerve impulses are stimulated by generation of action potential which is the movement of Sodium (Na+), the main extracellular cation and Potassium (K+), the main intracellular cation. Neuron is the functional unit of nervous system and of various shapes, size and types. It comprises primary structures- Soma, Dendrites, Axon and Terminal Buttons. Message propagates through terminal buttons in the form of signals. Major neurotransmitters are categorized into four groups: Acetylcholine, Monoamines, Amino acids and Peptides. Ach is released at synapses on skeletal muscles and can also be found in the ganglia of the autonomic nervous system, as well as the target organs of the parasympathetic nervous system. The substance is composed of Choline and Acetate, required for bioengineering. Monoamines includes four chemicals: Epinephrine, Norepinephrine, Dopamine and Serotonin. Serotonin belongs to class indolamines while others comes under catecholamines.^[7]Dopamine perform various functions associated with movement, attention and learning. Tyrosine is the precursor molecule for both dopamine and norepinephrine. The enzyme Monoamine oxidase (MAO) regulates the production of the catecholamines. MAO I found in the blood where it deactivates amines which could potentially cause dangerous increase in blood pressure. ^[1]

Parkinson is caused by the degeneration of dopaminergic neurons which serve to connect two parts of the brain’s motor system. Serotonin plays role in regulation of mood, control of eating, sleep and arousal; and regulation of pain. Various amino acids like Glutamic acid, GABA and Glycine shows both excitatory and inhibitory actions, but mostly inhibitory effect. As GABA is an inhibitory neurotransmitter, the effects of benzodiazepines, barbiturates and alcohol are the increase of neural inhibition. Alzheimer is a common age- related dementia distinct from vascular dementia associated with brain infarction. ^[18] Prion is a group of human and animal disease associated with a characteristic type of neurodegeneration, known as Spongiform encephalopathy ^[23][24] because of the vacuolated appearance of the affected brain has recently been the focus of intense research activity. ALS (Amylotropic lateral sclerosis) is a disorder of the motor neurons of the ventral horn of the spinal cord and the cortical neurons that provide their afferent input. Huntington is an inherited disorder resulting in progressive brain degeneration, starting in adulthood and causing rapid deterioration and death.

2. Review of literature
2.1 Alzheimer disease is a common age- related dementia distinct from vascular dementia associated with brain infarction
2.1.1 Pathophysiology ^{[14] [15] [30]}
The main pathological features of AD comprise amyloid plaques, neurofibrillary tangles and a loss of neurons (particularly cholinergic neurons of the basal forebrain). AD is the most common neuro degenerative disease in the United States. With an annual incidence of approximately 120 per 100,000 population. This is the commonest form of dementia. At autopsy, brains of AD victims shows these structural abnormalities- Loss of neurons that liberate acetylcholine- major centre of neuron that liberate Ach is the nucleus basalis, which is below the globus pallidus. Axons of these neurons project widely throughout the cerebral cortex and limbic system, their distribution is a hallmark of Alzheimer disease. β- amyloid plaques- clusters of abnormal proteins deposited outside neurons and neurofibrillary tangles- Abnormal bundles of filaments inside neurons in affected brain regions. These filaments consist of a protein called tau that has been hyperphosphorylated. These abnormalities and others contribute to a host of neurotoxic processes including oxidative stress and inflammation, failure of synaptic function, depletion of neurotransmitters and eventual cell death. AD is characterized by marked atrophy of the cerebral cortex and loss of cortical and sub cortical neurons. The term excitotoxicity was coined to describe the neural injury that results from the presence of excess glutamate in the brain. Glutamate is used as a neurotransmitter by many neural systems and is believed to mediate most excitatory synaptic transmission in the mammalian brain. Although Glutamate is required for normal braib function, the presence of excessive amounts of glutamate can lead to excitotoxic cell death. The destructive effects of glutamate are mediated by glutamate receptors, particularly those of the N-Methyl- D- Aspartate (NMDA) type. The proposed pathogenic mechanisms for AD generally comprise the basis for current attempts at therapeutic intervention.

2.1.2 Pharmacotherapy
These include loss of cholinergic function (cholinergic replacement therapy and neurotropins), oxidative stress (antioxidant therapy), the amyloid cascade (Aβ vaccine, β- and γ-secretase effectors, statins), inflammatory mediators (NSAIDS), steroid hormon deficiencies (hormone replacement therapy), excitotoxicity (memantine), and the role of dietary factors (low saturated fat diets, moderate alcohol intake. Cholinergic therapy, generally Acetylcholinesterase are the best- developed therapy and are used for mild to moderate disease. ^[29] The mechanism by which ACIs slow progression of disease is thought to be decreasing levels of β-amyloid protein precursor (AβPP) and production of αβ and amyloidogenic compounds. Tacrine was the first widely used ACI. Second generation cholinergics, including Donepezil ( trade name Aricept®, Eisai Company and Pfizer inc.), Galantamine (Hoechst Marion Roussel inc., Shire Pharmaceutical Group, and Janssen Pharmaceutical, trade names Reminyl® and Nivalin, U.S. trade name Razadyne) and Rivastigmine ( trade name Exelon®, Novartis Pharmaceuticals) have since been developed. These drugs have fewer side effects, longer half lives, and greater efficacy. Vitamin E in combination with vitamin C is also associated with a decrease in the prevalence and incidence of AD. Following are the current phase 3 clinical trial neuroprotective therapeutics so AD- Arovastatin, Ginko biloba, NSAIDS, Simvastatin, Tarenflurbil, Rosiglitazone, Tramiprosate, Xaliproden, Valproate, DHA, Docosahexanoic, LY2062430 Solanezumab, LY450139 Semagacestat, Dimebon Bapineuzumab and ELND005 (AZD-103). The mediterranean diet was recently demonstrated to be associated with lower AD risk. ^[19] A subsequent study has now shown that the Mediterranean diet is also associated with lower mortality in AD with a possible dose response effect. This diet is characterized by high intake of fish; a low- to-moderate intake of saturated fatty acids, moderately high intake of fish, low-to-moderate intake of dairy products, low intake of meat and poultry, and a moderate amount of ethanol. New trials including immunotherapy are in the attempt to avoid adverse T cell mediated immune response, many vaccination modalities under current investigation are directed towards the humeral response. Secretase effectors- Memapsin 2 (β-secretase, BACE1) is the protease that initiates cleavage of AβPP leading to the production of Aβ. FDA approved therapy with Donepezil, Rivastigmine and Glutamate is based on several large clinical studies in patients diagnosed with mild to moderate AD.^[4] Ladostigil is a multi- functional compound designed to incorporate the cognitive enhancing properties of Rivastigmine with the neuroprotection properties of Rasagiline. Dimebolin is a multifunctional drug enjoying a broad range activity profile on many targets relating to the treatment of AD. It is a weak acetyl cholinesterase (IC₅₀=7.9µM) and butyrylcholinesterases (IC₅₀=42µM) inhibitor. JWS-USC-75-IX (3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine) was found to possess AchEI activity help to cure AD.^[16] Besides Serotonin Receptors (5- hydroxytrptamine; 5-HT) are expressed throughout the peripheral and central nervous systems and are involved in a multitude of physiological functions such as cardiovascular and gastrointestinal regulation, thermoregulation, affective disorders as well as learning and memory. ^[5] Silent: 5-HT receptor antagonists (e.g., Lecozotan (SRA-333), NAD-299, WAY 100635 and WAY 101405) reverse anatomical lesions like (fornix and hippocampus) and pharmacological impairments.5 HT₃A receptor antagonists have also generated interest as putative cognitive enhancers given their ability to increase acetylcholine release and improve certain aspects of cognitive function; e.g., DAU 6215, Granisetron, Ondansetron, RS-56812, SEC 579 and WAY 100579. Phosphodiesterase (PDE) inhibitors (e.g., papaverine) were examined for their ability to increase cerebral blood flow in an attempt to improve cerebral metabolism and thereby, improve cognitive functions in aged patients. More recently, research has concentrated on the ability of PDE inhibitors to modulate the second messenger molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Some additional multifunctional compounds Memoquin resulted from a multi-targeted approach, combining the radical scavenger moiety of coenzyme Q (CoQ) with the polyamine backbone of caproctamine conferring AChE inhibition properties. It is becoming clear that Alzheimer disease is a multifactorial syndrome. ^[28] Development of therapies to alleviate the symptoms of degeneration is elucidated, this knowledge can be applied hopefully to prevent the disease or inhibit its progression. Several new directions in therapeutic approaches and that unraveling its causes may be difficult. However, as knowledge of the mechanisms are being investigated. ^[20]

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2.2 Parkinson disease is a progressive, age-related movement disorder, whose neuropathology is characterized by degeneration of the afferent pigmented neurons of the substantia nigra. Here we review oxidative stress mechanisms in PD, with emphasis on the relationship between oxidative stress and alpha synuclein gene expression. It leads to progressive deterioration of motor function due to loss of dopamine- producing brain cells. Primary symptoms include tremor, stiffness, slowness, impaired balance and later on a shuffling gait. Some secondary symptoms include anxiety, depression and dementia. Most individuals with Parkinson disease are diagnosed when they are 60 years old or older, but early-onset Parkinson also occurs. Parkinsonian syndromes can be divided into four subtypes according to their origin: Primary or idiopathic, Secondary or acquired, Hereditary Parkinsonism and Parkinson plus syndromes or multiple system degeneration. The most seriously affected brain area is basal ganglia.

2.2.1 Pathophysiology
There are five major pathways in the brain. Motor, oculo-motor, associative, limbic and orbitofrontal circuits which are affected badly. Dopamine depletion causes hypokinesia, an overall reduction in motor output. Abnormal accumulation of the protein alpha-synuclein bound to ubiquity in the damaged cells. This insoluble protein accumulates inside neurons forming inclusions called lewy bodies. This may leads to brain cell death if not treated on time. Lewy bodies are the protein aggregates in clumps. It arises sporadically which alters genetics. SNCA (synuclein, alpha non A4 component of amyloid precursor) makes the protein α-synuclein. These mutations are found in early- onset PD. While mutations in the PARK2 (Parkinson’s disease autosomal recessive, juvenile 2) gene makes the protein parkin. Parkin normally helps cells break down and recycle proteins. Genes- PARK7, PINK1 (PTEN-induced putative kinase 1), LRRK2 (leucine-rich repeat kinase 2) also shows mutations. Surgery is usually not considered for people who have dementia or psychiatric disorders. Other factors inducing PD are generation of free radicals, which are unstable molecules produced during normal chemical reactions in the body. When they interact with other molecules they have the ability to damage tissues like neurons. Aging is a normal decline of the dopamine producing neurons, which leads to the premature loss of dopamine. Several toxins like illegal drugs contaminated with a chemical called MPTP may cause severe Parkinson-like symptoms. It was found that once MPTP crossed into the brain it started killing brain cells. Other toxins are: Pesticides, Herbicides, manganese dust, carbon disulphide, carbon monoxide poisoning etc. ^[18][9][10]

2.2.2 Pharmacotherapy
While the treatment for PD is constantly improving, there is no single optimal treatment because the condition affects each individual differently. The symptoms can usually be effectively controlled, using a combination of therapies which may include the following: medication, adjunct therapies, such as physiology, occupational therapy, speech and language therapy and surgical treatment. Chemical treatment includes use of medications- Levodopa, which gets converted to dopamine in the body to replenish the deficiency of dopamine in the brain. It is given in the form of tablet or capsule. Combination of Levodopa and Carbidopa; like- Syndopa, Sinemet, Tidomet, LCD and Madopar (levodopa + benserazide) is used to reduce peripheral side effects.Dopamine agonists include- Bromocriptine (like- Proctinal and Parlodel), Carbergoline (like- Carberlin, Cabgol), Ropinirole (like- Requip, Ropark, Ropiro), Pramipexole (like- Pramipex, Pramirol, Lisuride (Dopergin). These are usually started at a low dose and increased slowly to reduce any possible side effects. Dopamine agonists are best taken with meals. Dopaminergics/Amantadine does several different things, but its main beneficial effect may be to promote the release of dopamine and to allow it to stay longer at its site of action. Anticholinergics (Pacitane, Kemadrine, Bexol) blocks the action of acetylcholine, a neurotransmitter that seems to work in balance with dopamine. Mono amine oxidase type (MAO-B) inhibitors inhibit the metabolism of dopamine by blocking the enzyme MAO-B; the enzyme that normally breaks down dopamine in the brain. COMT (catechol-O-methyl transferasr) inhibitors; Entacapone (Entacom, Adcapone, Comtan), Tolcapone (Tasmar) are a new class of medications and work by blocking an enzyme called COMT, which breaks down levodopa. These drugs are not to be given along with Pyridoxine, Phenothiazine, Butyrophenones, anihypertensives, domperidone as they abolishes therapeutic effects of levodopa. Cell therapy in which cells could survive, migrate and induce behavioral recovery of Parkinson symptoms, which were directly, related to reduced dopamine levels in the nigrostriatal system.^[13]After transplantation, cells could provide reparative and homeostatic microenvironment in vivo. Since time immemorial ayurvedic approach including fruits and vegetables, oil massaging, fomenting and cleansing. Herb, Atmagupta (Kappikachu) has been very effective for PD. Rigidity and low performance of nerves associated with Parkinson is treated wih nerve tonics such as Jatamansi and Shanka pushpin. A healthy and Mediterranean diet is also fruitful which includes high fibre foods, legumes, poultry, fish, low fat dairy products in diet.

2.3 Prion disease is a group of human and animal diseases associated with a characteristic type of neurodegeneration, known as Spongiform encephalopathy. It is transmissible through an infective agent. Different human forms of spongiform encephalopathy include CJD (which is unrelated to BSE) and the new variant form (vCJD), as yet very rare, which results from eating, or close contact with, infected beef or human tissue. Another human form is kuru, a neurodegenerative disease affecting cannibalistic tribes in Papua New Guinea. These diseases cause a progressive and sometimes rapid, dementia and loss of motor coordination, for which no therapies currently exist. Scrapie, a common disease of domestic sheep is another example.

2.3.1 Pathophysiology ^[21][9][10]
Protein misfolding disease in which the prion protein adopts a misfolded conformation that forms insoluble aggragates. The protein involved (PrP^C) is a normal cytosolic constituent of the brain and other tissues, whose functions are not known. As a result of altered glycosylation, the protein can become misfolded, forming the insoluble PrP^Scform, which has the ability to recruit normal PrP^C molecules to the misfolded PrP^Sc, thus starting a chain reaction leading to aggregation of insoluble fibrils in brain leading to neurodegeneration.

2.3.2 Pharmacotherapy ^[21]
There is yet no known treatment for this type of encephalopathy, but laboratory experiments suggest that two very familiar drugs, namely Quinacrine (an antimalarial drug) and Chlorpromazine (a widely used antipsychotic drug); can inhibit PrP^Scaggregation in mouse models. Both are under investigation for treating CJD.

2.4 Amyotrophic lateral sclerosis(ALS) is a disorder of the motor neurons of the ventral horn of the spinal cord and the cortical neurons that provide their afferent input. The ratio of males to females affected is approximately 1:5:1. Symptoms includes- Progressive weakness, muscle atrophy, Fasciculation, Spasticity, Dysarthria, Dysphasia, and respiratory compromise. It is characterized with Spasticity, which is defined as an increase an muscle tone characterized by an initial resistance to passive displacement of a limb at a joint, followed by a sudden relaxation (the so-called clasped-knife phenomenon).

2.4.1 Pathophysiology ^[9][10]
There is prominent loss of the spinal and brainstem motor neurons that project to striated muscles. Loss of the large pyramidal motor neurons in layer V of motor cortex, which is the origin of the descending corticospinal tracts. In familial cases, Clarke’s column and the dorsal horns sometimes are affected. About 10% ALS cases are familial (FALS), usually with an autosomal dominant pattern of inheritance. More than 90% of ALS cases are sporadic and are not associated with abnormalities of SOD1 or any other known gene. The cause of the motor neuron loss in sporadic ALS is unknown, but theories include autoimmunity, excitotoxicity, free radical toxicity and viral infection.

2.4.2 Pharmacotherapy
Riluzole (2- AMINO-6 [TRIFLUOROMETHOXY] benzothiazole; RILUTEK is an agent with complex actions in the nervous system. Riluzole is absorbed orally and is highly protein bound. Its half life is about 12 hours and undergoes extensive metabolism in the liver by both both cytochrome P450- mediated hydroxylation and glucuronidaion. Nausea, Diarrhoea, Hepatic injury with elevations of serum transaminases. Thus, periodic monitoring is needed. Other treatment approach is Symptometic treatment which includes Baclofen (Lioresal), a GABA-B receptor agonist, Tizanidine (Zanflex) is an agonist of α₂adrenergic receptors in the inhibition of motor neurons. Benzodiazepines such as Clonazepam (Klonipin) are effective antispasmodics. Dantrolene is also approved in the united states for the treatment of muscle spasm. Hepatotoxicity is the associated side effect.

2.5 Huntington disease is an inherited (autosomal dominant) disorder resulting in progressive brain degeneration, starting in adulthood and causing rapid deterioration and death. It causes severe motor symptoms in the form of involuntary writhing movements, which are highly disabling. ^[12]It is the commonest of a group of so-called trinucleotide repeat neurodegenerative diseases, associated with the expansion of the number of repeats of the CAG of the sequence in specific genes, and hence the number (50 or more) of consecutive glutamine residues in the expressed protein. Symptoms include- Movement disorder, Jerk like movements, brain. Fine motor in coordination, impairments of rapid eye movement, Slow mental processing, Paranoia and delusional states. Movements become more severe, dysarthia and dysphasia develops and balance is impaired.

2.5.1 Pathophysiology
HD is characterized by prominent neuronal loss in the striatum (caudate/putamen) of the brain. Atrophy of these structures proceeds in an orderly fashion, first affecting the tail of the caudate nucleus and then proceeding anteriorly from mediodorsal to ventrolateral. Selective vulnerability also appears to underlie the most conspicuous clinical feature of HD, the development of chorea. Its an autosomal dominant disorder with nearly complete penetrance. The average age of onset is between 35 and 40 years, but the range varies from as early as age 2 to as late as the middle 80s. Although inherited equally from mother and father, more than 80% of these developing symptoms before age 20 inherit the defect from the father. Disease can arise from unaffected parents, especially when one carries an intermediate allele. ^[9][10]

2.5.2 Pharmacotherapy
No current medication slows the progression of the disease and many medications can impair function because of side effects. Treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious or psychotic. Fluoxetine, Carbamazepine, Clozapine, Quetiapine, Tetrabenazine, Reserpine, Valproic acid are used to regulate associated deficits, which helps to cure HD upto certain extent.

3. Conclusion
Neurodegenerative diseases cannot be completely cured. This causes problems with movement (called ataxia), or mental functioning (called dementia). As we reviewed Alzheimer is the most common form of dementia. There is no cure for this disease, which worsens as it progresses, and eventually leads to death. No treatment can stop the disease. However, some drugs may help keep symptoms from getting worse for a limited time. A number of physical and chemical treatments are there to control them up to few extents. However, few drugs are still under research and clinical trials. Stem cell therapy is also in advancement and practice to treat the ailments.

Acknowledgement
Special thanks are extended towards my loving parents, sister and brother who continuously supported and guided me.

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