neurodegenerative disorders
TRANSCRIPT
PRESENTED BY
SHAHEEN BEGUM ,
M.PHARMACY (PHARMACOLOGY) ,
UCPSC,KAKATIYA UNIVERSITY ,
WARANGAL .
Overview Introduction
Mechanism of neuronal cell death
Selective vulnerability & Neuro-protective strategies
Classification of disorders
Details about each disorder
Pharmacotherapy
Recent advances
• Protein misfolding & Aggregation
• Excitotoxicity
• Necrosis
• Apoptosis
• Oxidative Stress
Mechanisms of Neuronal cell Death
Native protein
Misfoldedprotein
OligomerInsoluble
aggregates
Molecularchaperones
Mutation,External Factors
Cellular disposalmechanisms
Cellular deposits
Neurotoxicity
It is slowly progressing, extrapyramidal motor disorder
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.
Parkinson’s disease
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, ManganeseMercury
• Decreased DA content • Normal DA content• Decreased 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
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
Pathophysiology
Dopamine
⇓ MAO
DOPAC
⇓
H2O2
⇓ Fe++
Hydroxyl free radicals
⇓ Inadequate
protective mechanism
Degeneration of DA neurons
Wilsons Disease
Excitotoxicity
MPTP
Lewy bodies containing synuclein
Exposure to pesticides
Cigarette smoking
•Oxidative stress
Pathophysiology
Degeneration of darkly pigmented dopaminergic
neurons in SN
Loss of Dopamine in nigrostriatal tract
Lewy bodies(Intracellular
inclusion bodies)
Imbalance between inhibitory and
excitatory system
Corpusstriatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
Indirect pathway
Bradykinesia
TremorRigidity
Clinical features
Other motor features Non-motor features
Gait disturbance‘Shuffling gait’
Anosmia
Masked faceSensory disturbances (e.g., pain)
Reduced eye blinkMood disorders (e.g., depression)
Soft voice (hypophonia) Sleep disturbances
Dysphagia Autonomic disturbances
Freezing Cognitive impairment/Dementia
Micrographia
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
Pharmacotherapy
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
CNS-No effect in normal individuals. Symptomatic improvement in patients
CVS-Tachycardia, Hypotension
CTZ-Activates, elicits nausea and vomiting
Endocrine-Inhibits prolactin release to increse GH release
Pharmacological Actions
Pharmacokinetics Rapidly absorbed from the small
intestines
Undergoes first pass metabolism in GIT and liver
About 1% of administered levodopa enters brain
Plasma t1/2 is 1 to 2 hrs
Metabolites are excreted in urine
Bioavailability is effected by gastric emptying and presence of amino acids
Adverse effects Frequent and trouble some Dose related and reversible Nausea and vomiting
Occurs in almost every patient Hypotension
1/3 patient experience. Dizziness, fainting attacks occurs
CardiacarrhythmiasOccurs due to beta adrenergic action of DA
Alteration in taste sensations Dyskinesias Behavioural effects Fluctuation in motor performance
Other CNS side effects : Vivid dreams Hallucinations Sleep disturbances Confusion Miscellaneous : Mydriasis (may precipitate glaucoma attck) Abnormalities of taste, smell; hot flushes;
precipitates gout Increased blood urea, transaminases, ALP,
bilirubin
Recent advance in therapyRotigotine
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
ABLATIVE Thalamotomy, Pallidotomy
RESTORATIVE – Embryonic dopaminergic tissue
transplantation
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 with 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. • One who exercise regularly and aggressively have always seemed to have
done better.
Neuroprotection is perhaps best exemplified by strategies
designed to prevent cells undergoing apoptosis.
Cyclosporin A inhibits opening of the mitochondrial megapore, associated with loss of membrane potential and the start of apoptotic cell death.
Alzheimer’s Disease 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
Neuropathology Loss of neurons and synapses in the cerebral cortex and certain
subcortical regions.
Beta-amyloid plaque
Neurofibrillary tangles
Donepezil Rivastigmine Galantamine Tacrine
Enzymes inhibitedAChE 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 AD Mild–moderate AD, Mild–moderate AD Mild–moderate AD
Metabolism CYP2D6, CYP3A4 Esterases CYP2D6, CYP3A4 CYP1A2
Recent advancements in 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 metalshypothesis
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
Huntington’s disease Autosomal Dominant disorder
Characterized by –Choreic hyperkinesia
(dance-like movements of limbs & rhythmic movements of face & tongue)
Dementia with progressive
brain degeneration
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
EtiopathogenesisGenetic error in HUNTINGTIN GENE
⇓
Abnormal synthesis of Huntingtin protein
(Several repeats of polyglutamine)
⇓
Neuronal loss in striatum & cortex
⇓
Involuntary jerky movements
Neuropharmacological changes in HD
Degeneration 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 of
Choline 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
Drugs in pharmacotherapyDrug Mechanism Dose ADRs
Chlorpromazine Antipsychotic 1 mg orally BD
DA receptor antagonist
Behavioralchanges,Tolerance & dependence
Haloperidol Antipsychotic 1 mg orally BD
OlanzepineAtypical neuroleptic
10 mg orally OD
Tetrabenazine DA depletory12.5 – 25 mg orally TDS
Depression,Suicidal thoughts
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
Amyotrophic Lateral Sclerosis (ALS)“Ice-Bucket Challenge”
Etiology Defect in functioning of SOD (Superoxide dismutase)
↓ed uptake of glutamate by glutamate transporters
⇓
Overactivity of glutamate at NMDA receptors
⇓
Excitotoxicity
Pharmacotherapy Untreatable
Riluzole :
Recently approved
MoA:- Diminishes glutamate release & excitotoxicity
ADRs:- Nausea, dizziness, weight loss
Dose: - 50 mg BD
Tizanidine :
α – 2 agonist
Prevents post synaptic transmission
So, inhibits excess spasticity
ADRs: Dizziness, drowsiness
Beclofan
Gabapentin
Ceftriaxone
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 tanglesImplicated 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 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
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