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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 Protein
Folding 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
Misfoldedprotein
OligomerInsoluble
aggregates
Molecularchaperones
Mutation,External Factors
Cellular disposalmechanisms
Cellular deposits
Neurotoxicity
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 Incidence
Huntington’s disease • HuntingtinAutosomal Dominant
Alzheimer’s disease• APP• Presenilins
SporadicParkinson’s disease
• Dominant –α-synuclein, LRRK2
• Recessive –Parkin, PINK1, DJ-1
ALS • 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 bodies
α-Synuclein mutations occur in some types of familial Parkinson's disease
Huntington's disease Huntingtin No gross lesionsOne 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.
Parkinsonism
Primary 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 nigra
1939 Surgery at basal ganglia by Meyers
1957 Carlsson and colleagues discovered dopamine
1960 Ehringer and Hornykiewicz identified reduced dopamine in striatum
1961Levodopa 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 stress
Dopamine
⇓ MAO
DOPAC
⇓
H2O2
⇓ Fe++
Hydroxyl free radicals
⇓ Inadequate protective mechanism
Degeneration of DA neurons
Energy metabolism & Aging
• Increasing age ⇒ mutation in mitochondrial genome ⇒ ↓edcapacity 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
Corpusstriatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
Indirect pathway
Pathophysiology
Degeneration 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 faciesSensory disturbances (e.g., pain)
Reduced eye blinkMood 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
Bra
in B
arrier
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 meals
Gradually increased to 1 : 10 proportion thrice a day
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
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 Tolcapone
Peripheral action Central & peripheral actions
T1/2 2 hours T1/2 2 hours
Less potent More potent
Short duration of action Longer action
200 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
Bra
in B
arrier
L-dopa
DDC
MAO-B Dopamine
DOPAC
DA
D2
3-o-methyl dopa
Levodopa
3-o-methyl dopa
(Competes with l-dopafor uptake)
EntacaponeTolcapone
COMT
DDC Carbidopa
Dopamine
Does not cross BBBPeripheral degradationADRs
Brain
Peripheral tissue, Gut
Selegiline
Tolcapone
Bromocriptine
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 Loss
LanguageProblems
Mood andPersonalityChanges
DiminishedJudgement
Behavioral, Personality Changes
Unable to Learn orRecall New
Information
Long-Term MemoryAffected
Wandering, Agitation,Aggression, Confusion
Require Assistance with ADLs
Unstable Gait
Incontinence
Motor Disturbances
Bedridden
Dysphagia
Mute
Poor/No ADLs
Vacant
LTC 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 Neuropathology
BAPtists
• 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
⇓
“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 Tacrine
Enzymes inhibited AChE AChE, BuChE AChE AChE, BuChE
Mechanism Noncompetitive Noncompetitive Competitive Noncompetitive
Typical 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 ADMild–moderate AD,
Mild–moderate AD
Mild–moderate AD
MetabolismCYP2D6, CYP3A4
EsterasesCYP2D6, 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)
GSK188909non-peptidic BACE1 inhibitor
oralSignificant reduction in thelevel of Aβ40 and Aβ42 in the brain
PMS777Cholinesteraseinhibitor with anti-PAF activity
Decrease sAPPα secretion and Aβ42 release
γ-secretase inhibitors/modulators
DAPT,
BMS-299897
MRK-560
AD mice/ratsDecreased 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
Tarenflurbildouble 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
Deprenyl
Increases α-secretase activity bypromoting ADAM10 and PKCα/ε translocation
Neuroprotective agent
M1 muscarinic agonists
Decrease γ-secretase
Increase α-secretase activities
⇓
Decrease Aβ secretion
Decreased tau phosphorylation
• Inhibition of Aβ- and/or oxidative stress-induced cell death
M1 muscarinic agonists
Talsaclidine
Selective muscarinicM1agonist
Stimulates non-amyloidogenicα-secretaseprocessing in vitro
Decreased CSF Aβ by about 20%
AF102B M1 agonistDecreased CSF Aβof AD patients
AF267B In clinical trials
Aβ-aggregation inhibitors
iAβ5p β-sheet breaker
Intrahippocampalinjection 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
LY2062430
IVIG
against Aβ peptide
Phase II trials
Decreased cognitiveDecline
Slight improvement in functional scores
BapineuzumabMonoclonal Ab
Phase II, multicenter, randomized, double blind, placebo controlled clinical trials
Decreased tau levels in CSF without affecting Aβ level
Aβ Monoclonal Antibody Programs
BapineuzumabTargets AA 1-5;
IgG1
SolanezumabTargets AA 16-24; IgG1
PonezumabTargets 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
Clioquinol
Inhibits 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 inhibitor
Regulation of APP processing,
Inhibition of cell death markers andupregulation of neurotrophic factors
Ladostigil
Dual 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
Phenothiazines
Anthraquinones
Polyphenols
Thiocarbocyanine dyes
N-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 basalisof 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 timesG: 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
Corpusstriatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
Indirect pathway
HD
Neuropharmacological changes in HD
Degeneration of GABAergicneurons 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 ADRs
Chlorpromazine Antipsychotic1 mg orallyBD
DA receptor antagonist
Behavioralchanges,Tolerance & dependence
Haloperidol Antipsychotic1 mg orallyBD
OlanzepineAtypical neuroleptic
10 mg orally OD
Tetrabenazine DA depletory12.5 – 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.
Thank You