PHARMACOTHERAPY OF

NEURODEGENERATIVE DISORDERS

Dr. Jayesh Vaghela

Overview• Introduction• Mechanism of neuronal cell death• Selective vulnerability & Neuro-protective strategies• Classification of disorders• Details about each disorder• Pharmacotherapy• Recent advances

Mechanisms of Neuronal cell death

• Protein misfolding &Aggregation

• Excitotoxicity

Protein misfolding & Aggregation• Misfolding : Abnormal conformations of normally expressed

proteins ⇒ large insoluble aggregates

Linear AA chain

(Ribosomes)Functional

ProteinFolding correctly with specific AA located correctly

Conversion Requires

If goes wrong

Misfolded variantsCan’t find way to its

‘native’ conformation

Nonfunctional,Mischief in

cells

Native protein

Misfolded protein Oligomer Insoluble

aggregates

Molecularchaperones

Mutation,External Factors

Cellular disposal

mechanismsCellular deposits

Neurotoxicity

Excit

otox

icity

Selective Vulnerability & Neuroprotective Strategies

PD : - DA neurons of SN affected- Cortical neurons unaffected

AD : - Hippocampus & neocortex most affected- Even not uniform in cortex

HD : - Mutant gene expressed throughout brain, other organs- Pathological changes only in neostriatum

ALS : - Loss of spinal motor neurons & cortical neurons

Disorder Gene Mutations IncidenceHuntington’s disease • Huntingtin Autosomal

DominantAlzheimer’s disease • APP

• Presenilins

SporadicParkinson’s disease• Dominant –

α-synuclein, LRRK2• Recessive –

Parkin, PINK1, DJ-1ALS • SOD

Genetics & Environment

Disease Protein Characteristic pathology Notes

Alzheimer's disease β-Amyloid (Aβ) Amyloid plaquesAβ mutations occur in rare familial forms of Alzheimer's disease

 Tau Neurofibrillary

tangles

Implicated in other pathologies ('tauopathies') as well as Alzheimer's disease

Parkinson's disease α-Synuclein Lewy bodiesα-Synuclein mutations occur in some types of familial Parkinson's disease

Huntington's disease Huntingtin No gross lesions

One of several genetic 'polyglutamine repeat' disorders

Amyotrophic lateral sclerosis (motor neuron disease)

Superoxide dismutase(SOD)

Loss of motor neurons

Mutated superoxide dismutase tends to form aggregates; loss of enzyme function increases susceptibility to oxidative stress

Neurodegenerative Diseases Associated With Protein Misfolding And Aggregation

Parkinson’s disease

Introduction• Second most common neurodegenerative disorder in the

world• 5 million persons in the world • Prevalence rates in men are slightly higher than in women,

reason unknown, though a role for estrogen has been debated.

• Mean age of onset is about 60 years• Can be seen in 20’s and even younger.

ParkinsonismPrimary parkinsonism /Parkinson’s disease /

Paralysis agitans /Idiopathic parkinsonism

Secondary parkinsonism

• Group of various clinical features.

e.g. akathasia,unstable posture,Sialorrhea,Mask-like face, etc.

• Most patients suffer from primary parkinsonism

• Occurs from any known cause

• curable

• Genetic predisposition,• Aging of brain & free

radical injury

• Antipsychotic drugs e.g. D2 receptor antagonists

• Toxic - MPTP, CO, Mn• ↓ed DA content • Normal DA content

• ↓ed DA Activity• Blockade of postsynaptic

D2 receptors

HistoryYear Milestone

1817 J. Parkinson first described “An essay on the shaking palsy”

1841 Term ‘Paralysis agitans’ used for the first time by Marshall Hall

1888 Charcot referred the disease as Parkinson’s disease (PD)1919 Recognized Parkinsons having cell loss in substantia nigra1939 Surgery at basal ganglia by Meyers1957 Carlsson and colleagues discovered dopamine

1960 Ehringer and Hornykiewicz identified reduced dopamine in striatum

1961 Levodopa used for the first time in injectable form and a year later in oral form

1987 Deep-brain stimulation (DBS) was first developed in France

Etiology

Genetic factors• Mutation / over-expression of α-synuclein protein - autosomal

dominant parkinsonism⇓

• Protein misfolding and Aggregation

Oxidative stressDopamine

⇓ MAODOPAC

⇓ H2O2

⇓ Fe++

Hydroxyl free radicals ⇓ Inadequate protective mechanism

Degeneration of DA neurons

Energy metabolism & Aging• Increasing age ⇒ mutation in mitochondrial genome ⇒ ↓ed

capacity of neurons for oxidative metabolism• PD ⇒ several defects in energy metabolism, more than

expected with age• Most commonly, ↓ed function of complex-1 in ETC

Excitotoxicity• Glutamate excess

Environmental factors MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine),

a byproduct of manufacture of pethidine ⇓

Transported to CNS ⇓ MAO

MPP+ (methyle phenyle pyridine)⇓

Damage to DA neurons

Exposure to pesticides, rural living, drinking well-water

Cigarette smoking, caffeine ⇒ ↓ed incidence

Neurotransmitter Role

Cerebral cortex

Thalamus

STNSN-PR

GP-M

SN-PC

GPL

Corpusstriatum

Glu

GABA

GABA

GABA

Glu

GABA

GluDAD2 (-)

DAPD

Ach Ach

D1 (+)

Glu

Direct pathwayIndirect pathway

PathophysiologyDegeneration of

darkly pigmented dopaminergic neurons in SN

Loss of Dopamine in neostriatum

Lewy bodies(Intracellular

inclusion bodies)

Clinical Manifestations

Bradykinesia

TremorRigidity

Cardinal features

Other motor features Non-motor features

Gait disturbance‘Shuffling gait’ Anosmia

Masked facies Sensory disturbances (e.g., pain)

Reduced eye blink Mood disorders (e.g., depression)

Soft voice (hypophonia) Sleep disturbances

Dysphagia Autonomic disturbances

Freezing Cognitive impairment/Dementia

Micrographia

Pharmacotherapy

• Does not slow or prevent disease progression

• Improves quality of life

• 5-10% respond poorly to all medications

• AIM - Trying to stimulate the dopaminergic system and control the resulting excitation in cholinergic pathways

Classification Drugs affecting brain DA system :(a) Dopamine precursor : - Levodopa (l-dopa)(b) Peripheral decarboxylation inhibitors: - Carbidopa, Benserazide(c) Dopaminergic agonists: - Bromocriptine, Ropinirole,

Pramipexole(d) MAO-B inhibitor: - Selegiline(e) COMT inhibitors: - Entacapone, Tolcapone(f) Dopamine facilitator: - Amantadine

Drugs affecting brain Cholinergic system :(a) Central anticholinergics: - Trihexyphenidyl (Benzhexole),

- Benztropine mesylate,- Procyclidine,- Biperiden

(b) Antihistaminics : - Diphenhydramine

Levo - dopa ( L - dopa )• Precursor of dopamine

• Both therapeutic and adverse effects result from the decarboxylation of levodopa to dopamine

• 6-18 months to see improvement

Adverse Drug Reactions Fluctuations in response : “ Wearing-off effect ”• Duration of benefit is reduced as therapy progresses

“ On – Off Phenomenon ”• ‘On’ state : Normal mobility• ‘Off’ state : decreased mobility

Reason : Very short plasma T1/2 (1 – 2 hours)so rapid fluctuations in plasma concentration

Dyskinesias :• Excessive abnormal choreiform movements of limbs, trunk, face,

tongue• Occurs in high dosage long-term therapy

Other CNS side effects :• Vivid dreams• Hallucinations• Sleep disturbances• Confusion

Cardiovascular side effects :• Postural hypotension (release of DA in circulation)• Cardiac arrhythmia (cardiac α1 β1 receptors)

Peripheral side effects :• Anorexia, nausea, vomiting (CTZ stimulation by DA)

Miscellaneous :• Mydriasis (may precipitate glaucoma attck)• Abnormalities of taste, smell; hot flushes; precipitates gout• Increased blood urea, transaminases, ALP, bilirubin

Contraindications • Psychoses

• Narrow angle glaucoma

• Cardiac arrhythmias

• Melanoma (∵ levodopa is precursor of skin melanin)

Drug interactions• Pyridoxine (vit B6) - Increases metabolism of levodopa

- Decreases therapeutic effects• MAO-A inhibitors - Potentiate toxicity of levodopa

- Hypertensive crisis• Proteins in meals - Compete with transport

- ∴ Given 30 min before meals• TCA Antidepressant - Decreases absorption of levodopa

Blood Brain Barrier

L-dopa

DDC

MAO-B Dopamine

DOPAC

DA

D2

3-o-methyl dopa

Levodopa

3-o-methyl dopa

(Competes with l-dopafor uptake)

DDC Carbidopa

Dopamine

Does not cross BBBPeripheral degradationADRs

Brain

Peripheral tissue, Gut

COMT

LEVODOPA CARBIDOPA COMBINATION Advantages• The plasma T1/2 of levodopa is prolonged• Nausea and vomiting are not prominent• Cardiac complications are minimized.• “On-off” effect is minimized

Dosage : Carbidopa : Levodopa = 1 : 4 ration = 25 mg : 100 mg

3 times a day to be taken 30 min before mealsGradually increased to 1 : 10 proportion thrice a day

LEVODOPA CARBIDOPA COMBINATIONAdvantages

• The plasma T1/2 of levodopa is prolonged

• Nausea and vomiting are not prominent

• Cardiac complications are minimized

• “On-off” effect is minimized

Problems Not Solved

• lnvoluntary movements • Behavioral abnormality• Postural hypotension

Dopamine Agonists• Bromocriptine - Potent D2 receptor agonist

- Weak D1 antagonist• Cabergoline - Same as bromocriptine

- Longer acting (T1/2 > 80 hrs)• Ropinirole - D2 > D3, D4 Agonist• Pramipexole - Same as ropinirole

Advantages Do not require their conversion to DA

Do not depend on functional integrity of nigrostriatal neurons

Longer duration of action, lesser dyskinesia & ‘on-off’ phenomenon

More selective than levodopa on specific receptors

Less likely to generate damaging free radicals

Adverse Drug reactions• Anorexia, nausea, vomiting• Postural hypotension• Peripheral oedema• Digital / peripheral vasospasm• Vertigo• Erythromelalgia (red, tender, swollen joints of feet & hands)

Less frequent & less severe with pramipexole, ropinirole

COMT inhibitors• Dopamine 3-o-methyldopa (inactive)

⇓Inhibition of COMT causes more DA available

More plasma half life• Drugs are:

COMT

Entacapone TolcaponePeripheral action Central & peripheral actionsT1/2 2 hours T1/2 2 hoursLess potent More potentShort duration of action Longer action200 mg TID or QID 100 mg TDS

Reasons to combine Levodopa + COMT inhibitor Blockade of dopa decarboxylase by carbidopa

⇓Activates COMT mediated degradation of levodopa

Increased level of 3-o-methyldopa

3-o-methyldopa competes with levodopa to cross BBB⇓

Decreased therapeutic effect of levodopa

MAO – B inhibitor• MAO –B is principal enzyme responsible for metabolism of DA• Selegiline : Irreversible inhibitor of MAO-B• Early stages : - used alone• Later - with levodopa + carbidopa

- To reduce the need of levodopa• Neuroprotective role : Reduces the oxidative damage by free

radicals

• Desmethyl selegiline (metabolite) is responsible for neuroprotection & antiapoptotic effect

• ADR : - Insomnia

• Dose : - 5 mg with breakfast- 5 mg with lunch

Central Anticholinergic drugs• Block muscarinic receptors in striatum• Reduces striatal cholinergic activity

• Most commonly used for – Early stage of disease Late stage – as adjunct to levodopa + carbidopa therapy Neuroleptic-induced extrapyramidal side effects

• Interestingly, they correct tremors & rigidity more efficiently than other symptoms

• ADRs : dry mouth, urinary retention, blurred vision

Trihexyphenidyl :• Abuse potential• Patients display ‘fake’ signs to obtain the drug

Amantadine • Anti-viral drug• Dopamine facilitator

Mechanism : Prevents DA uptake Facilitates presynaptic DA release Weak antimuscarinic effects Blocks glutamate NMDA receptors

Treats PD symptoms

Reduces excitotoxicity

Uses :• Alone to treat early stage PD or

for patients who do not respond to levodopa• In combination with levodopa + carbidopa when more

beneficial response is required

ADRs:• Nausea, hallucination, insomnia, confusion, dizziness• Livedo reticularis (discolored area on skin due to passive

congestion)

Blood Brain Barrier

L-dopa

DDC

MAO-B Dopamine

DOPAC

DA

D2

3-o-methyl dopa

Levodopa

3-o-methyl dopa

(Competes with l-dopafor uptake)

EntacaponeTolcaponeCOMT

DDC Carbidopa

Dopamine

Does not cross BBBPeripheral degradationADRs

Brain

Peripheral tissue, Gut

Selegiline

TolcaponeBromocriptine

Amantadine

Other supportive drugs• Depression- Citalopram (or Amitriptyline)

• Dementia in ~30% with late disease• Treat as per dementia guideline

• Psychosis-low dose Clozapine or Quetiapine

Recent advance in therapy Rotigotine• Non-ergot DA agonist• D2, D3 receptor agonists• Transdermal patch formulation• Action : slows neurodegenerative process by D2 receptor

action• ADR : somnolence

Other DOPAMINE AGONIST :• Sumanirole – also neuroprotective

Surgery DEEP BRAIN STIMULATION• Often helpful in treatment of motor fluctuations• Most common type is deep brain stimulus of STN.• Acts like “electronic levodopa”.• Reduces tremor, rigidity and bradykinesia,• Allows reduction of l-dopa dose, but anti parkinsonism effect

no better than l-dopa except in tremors

OTHER SURGICAL PROCEDURES ABLATIVE • Thalamotomy, • Pallidotomy

RESTORATIVE –• Embryonic dopaminergic tissue transplantation

ADVERSE EFFECTS• Hemorrhage,

• Infection,

• Wire breakage,

• Speech impairment,

• Dystonia

Other newer modalities • Istradephylline Adenosine 2a receptor antagonist – anti parkinsonism effect

without dyskinesias.• Ns2330 – Triple monoamine reuptake inhibitor, i.e. dopamine, 5HT, NE

to help motor , cognition and depression

BOTULINUM TOXIN• In patients dystonias it is very beneficial and the results last

for 3 to 4 months. • Blepharospasm has always responded

NEUROTROPHIC FACTORS (NTF'S)• Substances that in and around our brain cells like glial derived

neurotrophic factor (GDNF) keep the cells functioning and healthy.

• Parkinson’s and other neurodegenerative diseases are a failure of endogenous neuroprotection.

• Practical way to increase GDNF is to exercise.

• Ones who exercise regularly and aggressively have always seemed to have done better.

NEUROPROTECTION• Neuroprotection is perhaps best exemplified by strategies

designed to prevent cells undergoing apoptosis.• Role of the mitochondria in the apoptotic pathway is also

receiving attention

• Cyclosporin A inhibits opening of the mitochondrial megapore, associated with loss of membrane potential and the start of apoptotic cell death.

• There is also evidence that selegiline have anti-apoptotic properties.

• A recent trial has begun with patients using ubiquinone as a means both to increase mitochondrial energy production and decrease free radical release

References• Standaert DG & Roberson E. Treatment of central nervous

system degenerative disorders.In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 609- 28.

• Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers medical publishers; 2009. p. 425-34.

• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 532-42.

• Olanow CW, Schapira AH. Parkinson’s disease and other movement disorder. In: LongoDL, editor :Harrisons’s principles of internal medicine.18th edition. New york:Mc Grew hill;2012. P.3317-35.

PHARMACOTHERAPY OF NEURODEGENERATIVE

DISORDERSPart – 2

Dr. Jayesh Vaghela

Overview• Alzheimer’s disease (AD)

• Huntington’s disease (HD)

• Amyotrophic Lateral Sclerosis (ALS)

Introduction • Dr. Alois Alzheimer in 1906

• An irreversible, progressive neurodegenerative disease that slowly destroys memory and thinking skills.

• Most common form of dementia.

• Risk increases with age

• In Most people symptoms first appear after age 60

The Stages of Alzheimer’s Disease

Mild Moderate Severe

Memory LossLanguage ProblemsMood and Personality ChangesDiminished Judgement

Behavioral, Personality ChangesUnable to Learn or Recall New InformationLong-Term Memory AffectedWandering, Agitation, Aggression, ConfusionRequire Assistance with ADLs

Unstable GaitIncontinenceMotor DisturbancesBedriddenDysphagiaMutePoor/No ADLsVacantLTC Placement Common

Stage

Symptoms

ADL = activities of daily living LTC = long-term care

STAGES OF AD

Neuropathology • Loss of neurons and synapses in the cerebral cortex and

certain subcortical regions.

Beta-amyloid plaques:

• Dense deposits of protein and cellular material

• Accumulate outside and around nerve cells

Neurofibrillary tangles:

• Twisted fibers that build up inside the nerve cells

Hypothesis regarding NeuropathologyBAPtists

• Accumulation of fragments of the amyloid precursor protein (APP)

⇓• Formation of plaques that

kill neurons

TAUists• Abnormal phosphorylation

of tau proteins makes them “sticky”

⇓• Break up of microtubules

⇓• Loss of axonal transport

causes cell death

Amyloid Hypothesis

‘Tau’ Hypothesis

t (tau) protein is a microtubule-associated protein that is responsible for stabilization of neurons

Phosphorylation ⇓“Paired Helical Filaments” or PHFs

(like two ropes twisted around each other)⇓

Accumulation &Formation of Neurofibrillary Tangles

⇓Impaired axonal transport

(probable cause of cell death)

Pharmacotherapy

Donepezil Rivastigmine Galantamine TacrineEnzymes inhibited 

AChE AChE, BuChE AChE AChE, BuChE

Mechanism Noncompetitive Noncompetitive Competitive NoncompetitiveTypical maintenance dose 

10 mg once daily 9.5 mg/24h (transdermal)

8-12 mg twice daily (immediate-release)

20 mg, four times daily

    3-6 mg twice daily (oral)

16-24 mg/day (extended-release)

 

FDA-approved indications Mild–severe AD Mild–moderate

AD,Mild–moderate AD

Mild–moderate AD

Metabolism CYP2D6, CYP3A4 Esterases CYP2D6, CYP3A4 CYP1A2

Recent Advances in treatment of AD

Drugs under investigation• Aβ-aggregation inhibitors• Aβ-degrading enzymes• Drugs influencing Aβ BBB transport• β-secretase inhibitors• γ-secretase inhibitors/modulators• α-secretase activators/modulators• M1 muscarinic agonists• Apolipoprotein E (ApoE)• Immunotherapy

• Drug development based on the metals hypothesis• HMG-CoA reductase inhibitors• MAO inhibitors• Treatments based on tau pathology• N-methyl-D-aspartate receptor (NMDA) antagonist• Non-steroidal antiinflammatory drugs (NSAIDs)• Estrogens, Nicotine, Melatonin• Cell transplantation and gene therapy• Docosahexaenoic acid (DHA), Clioquinol, Resveratrol

β-secretase inhibitors(β-site APP cleaving enzyme, BACE1)

GSK188909 non-peptidic BACE1 inhibitor oral

Significant reduction in thelevel of Aβ40 and Aβ42 in the brain

PMS777Cholinesteraseinhibitor with anti-PAF activity

Decrease sAPPα secretion and Aβ42 release

γ-secretase inhibitors/modulatorsDAPT,

BMS-299897

MRK-560

AD mice/rats Decreased Aβ levels in plasma and CSF

LY450139 dihydrate

randomized, controlled trial of 70 patients with mild to moderate AD

decreased 38% plasma and CSF Aβ40,

well tolerated

Tarenflurbil double blind placebo controlledPhase III study

no benefit on cognitive or functional outcomes, discontinued

α-secretase activators/modulators• α-secretase and β-secretase compete for the same substrate

of APP• Upregulation of α-secretase activity may decrease the

amount of APP available for β-secretase• Decrease Aβ secretion

α-secretase activators/modulatorsADAM 10

ADAM 17

ADAM 9

Adamalysinfamily of proteins

Overexpression of ADAM10 in transgenic mice showed less amyloid deposition in the hippocampus and lower Aβ levels in brain homogenate

Improved neurological function

TPPB Protein kinase C (PKC) activator

increases α-secretase activity and decreases Aβ secretion

SIRT1 Activates the gene code for α secretase ADAM10

suppress Aβ production in AD transgenic mice

DeprenylIncreases α-secretase activity bypromoting ADAM10 and PKCα/ε translocation

Neuroprotective agent

M1 muscarinic agonistsDecrease γ-secretase

Increase α-secretase activities⇓

Decrease Aβ secretionDecreased tau phosphorylation

• Inhibition of Aβ- and/or oxidative stress-induced cell death

M1 muscarinic agonists

TalsaclidineSelective muscarinic M1agonist

Stimulates non-amyloidogenic α-secretaseprocessing in vitro

Decreased CSF Aβ by about 20%

AF102B M1 agonist Decreased CSF Aβof AD patients

AF267B In clinical trials

Aβ-aggregation inhibitors

iAβ5p β-sheet breaker

Intrahippocampal injection improved spatial memory and decreased amyloid plaque deposits

Immunotherapy

New modified vaccines

Novel peptide-carrier protein using an amino terminal fragment of Aβ are under developmentto avoid potentially harmful T-cell responses

Maintain a similar antibody response to that ofAN1792

LY2062430IVIG

against Aβ peptide

Phase II trials

Decreased cognitiveDecline

Slight improvement in functional scores

Bapineuzumab

Monoclonal Ab

Phase II, multicenter, randomized, double blind, placebo controlled clinical trials

Decreased tau levels in CSF without affecting Aβ level

Aβ Monoclonal Antibody Programs

Bapineuzumab Targets AA 1-

5; IgG1

Solanezumab Targets AA 16-24; IgG1

Ponezumab Targets AA 33-40; IgG2Da

N-Terminus C-Terminus

Ganteneruzumab targets Aβ aggregates

Drugs influencing Aβ BBB transport• Receptor for advanced glycation end products (RAGE)

• Resides in the blood vessel wall cells• Transports Aβ across the blood brain barrier from systemic

circulation to facilitate their accumulation in brain ⇒ Dangerous

• Low density lipoprotein receptor related protein 1 (LRP-1)• Mediates transport of Aβ peptide out of brain• ⇒ Protective

Alzheimer’s Disease⇓

↑ RAGE and ↓ LRP-1⇓

Inhibition of RAGE &Activation of LRP-1

⇓Therapeutic Targets

Drug development based on the metals hypothesis

ClioquinolInhibits zinc and copper ions from binding to Aβ

Phase II clinical trial

Improved cognitive function

Decreased plasma Aβ42 level and zinc concentration

XH1, DP-109, PBT2 Metal chelators

Improved cognitive function and decreasedCSF Aβ42 compared with placebo

But not plasma Aβ

HMG-CoA reductase inhibitors• Statins ⇒ ↓ed Incidence of AD• CH-rich diet⇒ ↑ β-secretase processing of APP• CH less diet⇒ ↓ Aβ production

• Atorvastatin and lovastatin: clinical benefit in AD patients

Monoamine oxidase inhibitors

Rasagiline MAO-B inhibitorRegulation of APP processing,

Inhibition of cell death markers andupregulation of neurotrophic factors

LadostigilDual AchE & BuChEAndBrain selectiveMAO-A and -B inhibitor

Regulate APP processing

Treatments based on tau pathologyLithium,AF267B,Propentofylline (PPF),SRN-003 & 556

Prevented thehyperphosphorylation of tau

PhenothiazinesAnthraquinonesPolyphenolsThiocarbocyanine dyesN-Phenylamines,Thiazolyl-hydrazides,Rhodanines,Quinoxalines,Aminothienopyridazines

Prevent tau protein aggregation

Targeting tauchaperones

Prevent themisfolding of tau

Phosphorylated tau antigens

Reduction in soluble and insoluble phosphorylated tau

Significant attenuation of cognitiveimpairment

N-methyl-D-aspartate receptor(NMDA) antagonist

Memantine-

• Low to moderate affinity noncompetitive NMDA receptor antagonist for the treatment of moderate to severe AD

• Restores the function of damaged nerve cells and reduce abnormal excitatory signals by the modulation of the NMDA receptor activity

• Improvement in cognitive, functional, and global outcomes

Non-steroidal Anti-inflammatory Drugs (NSAIDS)

• Association between NSAID use and a lower incidence of AD

• Adverse effect in later stages of AD pathogenesis

• Asymptomatic individuals treated with naproxen experience reduced AD incidence, but only after 2 to 3 years

Estrogens• Neuroprotective against oxidative stress, excitatory

neurotoxicity, and ischemia in the brain• Antioxidant, antiapoptotic, neurotrophic and

antiamyloidogenic activities• Activate matrix metalloproteinases-2 and −9 to increase beta

amyloid degradation• Withdrawal of estrogen in postmenopausal women-

predisposition to AD• Use of estrogen during HRT- neuroprotective• Premarin, raloxifen- in phase II

Nicotine• Cholinergic agonist- acts both post and pre-synaptically to

release ACh

• AD: ↓ed Nicotinic receptor density

• Nicotine- ↑es neurone survival in neurotoxic insults

• Improvements in cognitive tasks such as recall, visual attention and perception and mood

Melatonin• Tryptophan metabolite, synthesized by pineal gland

• Regulates circadian rhythms, clears free radicals, improves immunity, and inhibits the oxidation of biomolecules

• Important in mechanisms of learning and memory

• Melatonin deficit- related to aging and age related diseases

• Prevents neuronal death caused by exposure to the amyloid beta protein

• Inhibits the aggregation of the amyloid beta protein

• Prevents the hyperphosphorylation of the tau protein

• Melatonin supplementation has been suggested to improve circadian rhythmicity, and to produce beneficial effects on memory

Cell transplantation and gene therapy• Degeneration of the cholinergic neurons in the nucleus

basalis of Meynert- reduction in the cholinergic innervation in the cortical and subcortical regions

• In AD rat model, transplantation of cholinergic rich tissue or peripheral cholinergic neurons ameliorates abnormal behaviour and cognitive function

• No clinical trials have been initiated• Nerve growth factor (NGF)- rescues neurons from cell damage

and leads to memory improvements

Docosa hexaenoic acid (DHA)• Increased intake of the DHA is associated with a reduced risk

for AD• Antiamyloid, antioxidant, and neuroprotective mechanisms• Positive effect in patients with very mild AD

Resveratrol• Red wine polyphenol

• Protects against CVD, cancers

• Promotes antiaging effects

• Inhibits Aβ aggregation, by scavenging oxidants and exerting anti-inflammatory activities

• Slows down AD development

Marijuana Compound a Novel Treatment for Alzheimer's ?

• Extremely low levels of delta-9-tetrahydrocannabinol (THC), the active compound in marijuana

⇓• may offer a novel and viable treatment for Alzheimer's

disease (AD)

• Under research

Huntington’s

Disease

Introduction • Autosomal Dominant disorder• Characterized by – Choreic hyperkinesia

(dance-like movements of limbs & rhythmic movements of face & tongue)

Dementia with progressive brain degeneration• Prevalence rate = 1 : 10,000

GENETICS: All human have 2 copies of huntingtin gene (HTT) which

codes for protein called huntingtin (htt).

Also called HD gene and IT15 (interesting transcript 15)

HUNTINGTIN GENE:• Located on short arm of chromosome 4• It contains a sequence of 3 DNA base:

C: cytosine A: adenine Repeated multiple times G: guanine (CAGCAGCAGCAG) Known as TRINUCLEOTIDE REPEAT

This repeated part of gene is known as POLY Q region

CAG: It provides genetic code for amino acid GLUTAMINE. So repetition of this gene cause production of chain of glutamine Known as POLYGLUTAMIC TRACT

  Generally people have < 36 repeated glutamine in poly Q region

HUNTINGTIN PROTEIN• It regulates gene expression• Functional role in cytoskeleton anchoring and transport of

mitochondria• Interacts with protein HIP1 (A clathrin binding protein to mediate

endocytosis)• Major role in shaping rounded vesicles• Protects neurons• High conc. brain• Moderate conc. liver, heart and lung

Etiopathogenesis Genetic error in HUNTINGTIN GENE

⇓Abnormal synthesis of Huntingtin protein

(Several repeats of polyglutamine)⇓

Neuronal loss in striatum & cortex⇓

Involuntary jerky movements

Cerebral cortex

Thalamus

STNSN-PR

GP-M

SN-PC

GPL

Corpusstriatum

Glu

GABA

GABA

GABA

Glu

GABA

GluDAD2 (-)

DAPD

Ach Ach

D1 (+)

Glu

Direct pathwayIndirect pathway

HD

Neuropharmacological changes in HDDegeneration of GABAergic

neurons in striatum⇓

75% reduction in activity of Glutamate decarboxylase

(enzyme responsible for GABA synthesis)

⇓Loss of GABA mediated inhibition

in basal ganglia⇓

Hyperactivity of DA neurons

Decreased concentration ofCholine acetyl transferase

(Enzyme responsible for synthesis of ACh)

⇓Decreased Cholinergic activity

Clinical Features

• Impaired intellectual functioning

• Interfere with normal activities

• Less ability to solve the problems

• Agitation and sleeping disturbance.

• Progressive mental deterioration

Patient eventually become totally dependent

• loss of musculoskeletal control.

• Tongue smacking

• Dysarthia: indistinct speech

• Bradykinesia: slow movement

• Dysphagia: mostly occur in advanced stage. It is difficulty in swallowing or feeling that food is sticking in your throat or chest. This lead to weight loss following malnutrition

Treatment Strategy: Replacing the missing neurotransmitter• GABA receptor agonists, or All are• GABA degradation inhibitors Not effective• Choline chloride therapy

Surprisingly, Adjusting DA / ACh balance has proved

more effective Done by antagonizing DA overactivity

Drugs Drug Mechanism Dose ADRsChlorpromazine Antipsychotic 1 mg orally BD

DA receptor antagonist

Behavioral changes,Tolerance & dependence

Haloperidol Antipsychotic 1 mg orally BD

Olanzepine Atypical neuroleptic

10 mg orally OD

Tetrabenazine DA depletory 12.5 – 25 mg orally TDS

Depression,Suicidal thoughts

AmyotrophicLateralSclerosis (ALS)Lou Gehrig disease

Introduction • Progressive neurodegenerative disorder of motor neurons• Muscle wasting & Atrophy (∴ Amyotrophic)

• Clinically, Starts with spontaneous twitching of motor units, Difficulty in chewing & swallowing Respiratory failure leads to death within 2 – 5 years

Etiology Defect in functioning of SOD (Superoxide dismutase)

↓ed uptake of glutamate by glutamate transporters⇓

Overactivity of glutamate at NMDA receptors⇓

Excitotoxicity

Treatment • Untreatable

Riluzole :• Recently approved• MoA: - Diminishes glutamate release & excitotoxicity• ADRs: - Nausea, dizziness, weight loss• Dose: - 50 mg BD

Baclofen • GABA-B agonist• Indication: Muscle spasticity• Dose: 5 – 10 mg orally OD• Intrathecal catheter also available• ADRs: Life-threatening depression• Advantage: No / minimal sedation

Tizanidine • α – 2 agonist • Prevents post synaptic transmission• So, inhibits excess spasticity• ADRs: Dizziness, drowsiness

Other drugs Gabapentin:• Slows decline in muscle strength

Ceftriaxone:• 3rd generation cephalosporin• ↑es glutamate uptake• Anti excitotoxic

“Ice-Bucket Challenge” Raising awareness

about ALS Accept the

challenge or Donate or do both

References• Standaert DG & Roberson E. Treatment of central nervous

system degenerative disorders.In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 609- 28.

• Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers medical publishers; 2009. p. 425-34.

• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 532-42.

• Olanow CW, Schapira AH. Parkinson’s disease and other movement disorder. In: LongoDL, editor :Harrisons’s principles of internal medicine.18th edition. New york:Mc Grew hill;2012. P.3317-35.

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