This document provides an overview of various neurodegenerative diseases and their pharmacotherapy. It discusses the mechanism of neuronal cell death including protein misfolding and aggregation, excitotoxicity, and apoptosis. Several neurodegenerative diseases are then examined in more detail, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and others. For each disease, the document discusses aspects such as pathology, genetics, clinical features, and pharmacotherapy options.

1. Dr Sneha Dange, JR3
Dept of Pharmacology,
GMCH, Nagpur

2. Overview :
2
 Introduction
 Mechanism of neuronal cell death
 Various neurodegenerative diseases –
 Pharmacotherapy of each disease
 Conclusion
o Alzheimer’s diseas
o Parkinson’s disease
o Amyotrophic lateral sclerosis
o Huntington’s disease
o Multiple sclerosis
o Wilson’s disease
o Prion diseases

3. 3
Introduction :
 Dead neurons in adult central nervous system are not replaced
nor their terminals can regenerate when axons are interrupted
 Any pathological process causing neuronal death has
irreversible consequences
 Incidence & social impact of neurodegenerative brain disorders
in ageing populations have resulted in massive research effort
in recent years

4. 4
Mechanism of neuronal cell death :
Protein misfolding & aggregation
Excitotoxicity
Apoptosis & oxidative stress

5. Selective Vulnerability :
5
† Alzheimer’s disease : injury in hippocampus & cortex
† Parkinson’s disease : loss of nigrostriatal dopaminergic neurons
† Amyotrophic lateral sclerosis : degeneration of spinal, bulbar & cortical neurons
† Huntington’s disease : GABAergic striatonigral pathway is impaired
† Multiple sclerosis : impairment of nerve conduction due to demyelination of neurons

6. Genetics & Environment :
6
Disorder Gene Mutations Incidence
Huntington’s disease Huntingtin Autosomal Dominant
Alzheimer’s disease APP, Presenilins Sporadic
Parkinson’s disease • Dominant –
α-synuclein, LRRK2
• Recessive –
Parkin, PINK1, DJ-1
Amyotropic lateral sclerosis SOD

7. Neurodegenerative Diseases Associated With Protein
Misfolding And Aggregation:
7
Disease Protein Characteristic pathology
Alzheimer's disease β-Amyloid (Aβ)
Tau
Amyloid plaques,
Neurofibrillary tangles
Parkinson's disease α-Synuclein Lewy bodies
Huntington's disease Huntingtin No gross lesions
Amyotrophic lateral
sclerosis (motor
neuron disease)
Superoxide dismutase
(SOD)
Loss of motor neurons

8. 8
Alzheimer’s disease

9. Alzheimer’s disease (AD) :
* An irreversible, progressive neurodegenerative disease that slowly destroys
memory & thinking skills
* Does not have an antecedent cause, such as stroke, brain trauma or alcohol
* Prevalence rises sharply with age, from about 5% at 65 years to 90% above 95 years
of age
* Can manifest as early as the 3rd decade of life, but is the most common cause of
dementia in the elderly
9

10. Alzheimer’s disease contd..
10
Risk Factors :
 Increasing age
 Female gender
 Family history
 APP, PSEN 1 & 2 genes,
ApoE4
 Education
 CVS disease DM
 Vit A,C,E deficiency
Cardinal features :
 Progressive loss of memory
 Disordered cognitive functions
 Loss of short term memory
 Loss of long term memory

11. Pathology :
11
* Amyloid plaque, extracellular deposits of beta-amyloid protein (Aβ) in cortex,
hippocampus, amygdala & subcortical nuclei
* Intraneuronal neurofibrillary tangles which comprise of aggregates of highly
phosphorylated form of normal neuronal protein (Tau)
* Most striking neurochemical disturbance is a deficiency of Acetylcholine due to
atrophy and degeneration of subcortical cholinergic neurons
* Mutations in three genes identified as causes of autosomal dominant – APP, PSEN1
& PSEN2, ε4 allele of APOE have more than 3-fold higher risk
Alzheimer’s disease contd..

12. 12
Alzheimer’s disease contd..
Cholinesterase
inhibitors
• Tacrine
• Donepezil
• Rivastigmine
• Galantamine
NMDA
antagonists
• Memantine
Others
• NSAID
• Secretase
inhibitors
• Statins
• Gingo biloba
Pharmacotherapy :

13. 13
Cholinesterase inhibitors :
* Tacrine - first drug approved to treat AD but is rarely used now (hepatotoxicity)
* First-line therapy for symptomatic treatment of cognitive impairment in mild or
moderate AD (early stages of disease)
* Their effect is generally modest & 6 to 12 month delay in progression
* Most common side effects - GI distress, muscle cramping & vivid dreams
Silent features :
Alzheimer’s disease contd..

14. 14
Cholinesterase inhibitors :
* Tacrine - first drug approved to treat AD but is rarely used now (hepatotoxicity)
* First-line therapy for symptomatic treatment of cognitive impairment in mild or moderate AD
(early stages of disease)
* Donepezil (10 mg daily), Rivastigmine (6 mg twice daily or 9.5-mg patch daily) & Galantamine (24
mg daily, extended-release) are widely used for this purpose
* Their effect is generally modest, 6 to 12 month delay in progression
* Most common side effects - GI distress, muscle cramping & abnormal dreams
Alzheimer’s disease contd..

15. 15
Memantine :
* Noncompetitive antagonist of the NMDA-type of glutamate receptor
* It interacts with Mg2+ binding site of channel to prevent excessive activation
* Used either as adjunctive or alternative to cholinesterase inhibitors in moderate
to severe cases
* delays clinical deterioration in patients with moderate-to-severe AD dementia
* Adverse effects - headache or dizziness
Pharmacotherapy Alzheimer’s disease contd..
5mg OD
increased to
10-20mg/day

16. 16
Pharmacotherapy Alzheimer’s disease contd..
* NSAIDs & Statins have been associated with significantly reduced risk of AD
* Extract of Gingo biloba have modest improvement in cognitive function in AD but no
slowing of disease progression
* Tarenflurbil modulates γ-secretase to produce less of the toxic form(Aβ42)- negative
results
* Vaccine against Aβ 42 highly efficacious in mouse model- clear amyloid & its
accumulation
* Medications that modify tau phosphorylation and aggreagation like tau abs are beginning
to be studied

17. 17
Parkinson’s
disease

18. Definition :
18
Parkinson's disease (PD) is a progressive degenerative disorder, mostly affecting
older people, first described by James Parkinson in 1817 as paralysis agitans or the
“shaking palsy”
4 cardinal features:
 Bradykinesia
 Muscular rigidity
 Resting tremor
 Impairment of postural
balance, disturbances of
gait and falling
Pathological Hallmark
 loss of the pigmented,
dopaminergic neurons of
the SNPC, with the
appearance of intracellular
inclusions(Lewy
bodies)aggregated α-
synuclein

19. Etiology :
19
Parkinson’s disease contd….
* Dominant (α-synuclein, LRRK2) and recessive (parkin, DJ-1,
PINK1) gene mutations
* Ageing, oxidative generation of free radicals, N-methyl-4-phenyl
tetrahydropyridine (MPTP)-like environmental toxins and
excitotoxic neuronal death due to NMDA-receptor (excitatory
glutamate receptor) mediated Ca2+ overload
* The dopaminergic deficit due to loss of the neurons in the
substantia nigra pars compacta that provide innervation to the
striatum

20. 20
Drugs affecting brain dopaminergic
system :
Dopamine precursers : levodopa
Dopamine Receptor Agonists : ropinirole and
pramipexole, Rotigotine
COMT inhibitors : tolcapone and entacapone
Peripheral decarboxylase inhibitors : Carbidopa and
benserazide
MAO-B inhibitor : Selegiline, rasagiline
Glutamate (NMDA receptor) Antagonist (dopamine
facilitator) : amantadine
Parkinson’s contd….
Drugs affecting brain
cholinergic system :
Central anticholinergics :
Trihexyphenidyl, Procyclidine,
Biperiden
Antihistaminis : Orphenadrine,
Promethazine

21. 21
Pharmacotherapy of Parkinson’s disease :
Levodopa - the metabolic precursor of DA & is absorbed rapidly from the small
bowel
* Rapidly absorbed from gut, t½ is 1-2 hrs
* More than 95% of an oral dose is decarboxylated in the peripheral tissues & 1-2%
crosses to the brain
* Co-administered with either Carbidopa/ Benserazide (peripheral decarboxylase
inhibitors) available as 25/100, 10/100 , 25/250 form tablets daily

22. Adverse effects :
22
† Nausea and vomiting, postural hypotension and tachycardia
† Exacerbation of angina, Cardiac arrhythmias
† Alteration in taste sensation, peptic ulcer, glaucoma and gout
† Abnormal movements (dyskinesias) facial tics,grimacing,choreoathetoid
movements of limb
† Mild anxiety, nightmares, severe depression, mania, hallucinations, mental
confusion, Frank psychosis
† Fluctuation in motor performance- “wearing off” & “on and off ”
Pharmacotherapy of Parkinson’s dis contd….

23. Advantages of combination :
23
 The plasma t½ of levodopa is prolonged and dose is reduced to approximately I/4th
 Systemic concentration of DA is reduced - nausea and vomiting are minimized
 therapeutic doses of levodopa can be attained more quickly
 Cardiac complications are reduced
 “On-off” effect is minimized since cerebral DA levels are more sustained
 Degree of improvement may be higher; some patients not responding adequately to
levodopa alone, also improve.
Pharmacotherapy of Parkinson’s dis contd….

24. Dopamine agonist :
24
 The DA agonists act on DA receptors
 Used to reduce “off” time in advanced cases
 Less prone to develop dyskinesia – useful in younger patients
Ropinirole(0.25mg TDS) and Pramipexole (0.125mg)–
 Nonergoline, selective D2/D3 receptor agonists
 used for monotherapy in early PD also to supplement levodopa-carbidopa in
advanced cases
 Ropiniorol, Pramipexol – oral(tid) extended release, Rotigotine - once daily
transdermal patch
 Apomorphine – parenterally or SC inj as rescue agent for severe off episode
 Bromocriptine (1.25mg HS)–
 It is an ergot derivative
 potent agonist of D2 receptors
 Improvement in symptoms occurs within ½-1 hour and lasts for 6-10 hours
 doses needed are high
 Side effects- vomiting, hallucinations, nasal stuffiness, marked fall in BP,
cardiac valvular damage, pulmonary fibrosis
Pharmacotherapy of Parkinson’s dis contd….

25. Catechol-O-Methyl Transferase inhibitors
(COMT inhibitors) :
25
Parkinson’s contd….
* Selective, potent and reversible COMT inhibitors
* Adjuvants to levodopa-carbidopa, prolongs the t½ of levodopa,
reduction in levodopa dose
* No benefit in early PD cases
* Entacapone acts peripherally, tolcapone (hepatotoxic) acts on
both sides
* Adverse effects- nausea, vomiting, dyskinesia, postural
hypotension, hallucinations
Entacapone(200 mg)
Tolcapone(100 mg)
 Uses - in advanced PD
with motor
fluctuations
 Used to smoothen
“wearing off”
increase “on” time,
decrease “off” time.

26. MAO-B inhibitors :
26
* Selegiline, Rasagiline- selective and irreversible MAO-B inhibitor – mild effect in
early cases
* As adjuvant to levodopa- prolongs levodopa action, reduction in levodopa dose,
attenuates motor fluctuations and decreases “off“ time
* might delay progression of the disorder
* Postural hypotension, nausea, confusion, involuntary movements and psychosis
* Safinamide- reversible, approved as adjunctive also blocks activated Na+ channel &
inhibit glutamate release, currently being studied as antidyskinetic agent
Selegiline
5mg-10mg BD
Rasagiline
(1mg) OD
Pharmacotherapy of Parkinson’s dis contd….

27. Central anticholinergics :
27
* Were used historically for parkinsonian symptoms, Tremor is benefited more than
rigidity, hypokinesia is improved the least
* Efficacy is much lower than levodopa but is inexpensive
* Limited use in elderly – urinary dysfunction, glaucoma, cognitive impairement
* May be used alone in mild cases or when levodopa is contraindicated, Only drugs
effective in drug induced parkinsonism
* Eg., Trihexyphenidyl, procyclidine, biperiden, orphenadrine, promethazine
Pharmacotherapy of Parkinson’s dis contd….

28. Glutamate antagonist :
Amantadine
* an antiviral drug for prophylaxis of influenza A
* promotes presynaptic synthesis and release of DA in the brain
* has an antagonistic action on NMDA type of glutamate receptor
* used in elderly in mild cases or as antidyskinetic agent in advanced cases
* Fixed dose of 100 mg BD is used, the effect lasts 8- 12 hours; 28
Pharmacotherapy of Parkinson’s dis contd….

29. 29
Pharmacotherapy of Parkinson’s dis contd….
* Istradefylline - an adenosine receptor antagonist, FDA approved drug as an adjunctive
* Surgical treatment - involving implantation of device called brain pace maker which
sends electrical impulses to specific parts of the brain (Target areas STN & Gpi)
* DUOPA- infusion pump having enteral suspension 4.63 mg carbidopa and 20 mg levodopa
per mL in a single-use cassette. At the end of the daily 16-hour infusion, patients will
disconnect the pump & take their night-time dose of oral immediate-release carbidopa-
levodopa tablets
* Recommended for patients with motor fluctuations in advanced disease
* Stem cell therapy- showed human embryonic stem cells to produce a new generation of
dopamine cells that behave like native dopamine cells when transplanted into the brains
of rats

30. 30
Huntington’s disease

31. Huntington’s disease
31
* HD is a progressive, fatal, highly penetrant, autosomal dominant disorder
characterized by motor, behavioral, oculomotor & cognitive dysfunction
* Average age of onset is 35-45 years, death ~20 years later but varies from 2 to
80 years
* Characterized by rapid, nonpatterned, semi-purposeful, involuntary choreiform
movements
* With advancing disease, there tends to be a reduction in chorea and the
emergence of dystonia, rigidity, bradykinesia & myoclonus

32. Huntington’s disease contd…
32
* Depression with suicidal tendencies, aggressive behavior & psychosis
* Disease predominantly affects the striatum but progresses to involve the cerebral
cortex
* Genetics - A region near the end of the short arm of chromosome 4 contains a
polymorphic (CAG) trinucleotide repeat encodes huntingtin protein- expanded in all
individuals with HD
* The larger the number of repeats, the earlier the disease is manifest
* Mitochondrial dysfunction has been demonstrated in the striatum and skeletal muscle

33. Etiology :
 Degeneration of GABAergic neurons in
striatum leads to 75% reduction in
activity of Glutamate decarboxylase
(enzyme required for synthesis of
GABA)
Loss of GABA mediated inhibition in basal
ganglia
Hyperactivity of DA neurons
33
↓ Concentration of Choline
acetyl transferase (enzyme
required for synthesis of ACH)
↓ Cholinergic activity
Huntington’s disease contd..

34. Treatment :
34
* There is still no disease-modifying therapy for this disorder
* Current treatment involves a multidisciplinary approach, with medical,
neuropsychiatric, social, and genetic counseling for patients and their families
* Tetrabenazine(12.5 mg daily) -inhibitors of VMAT2 cause presynaptic depletion
of catecholamines
* DA receptor antagonists chlorpromazine, haloperidol (1g BD) & atypical
neuroleptics olanzepine (10mg daily)
* Both drugs may cause hypotension and depression with suicidality
Huntington’s disease contd..

35. 35
* Drugs that enhance mitochondrial function & ↑ clearance of defective
mitochondria are being tested as possible disease-modifying therapies
* Areas of active research : Antiglutamate agents, dopamine stabilizers, caspase
inhibitors, neurotrophic factors & transplantation of fetal striatal cells or stem
cells or DBS of globus pallidus
* Transcriptional blockade of mutant huntingtin gene with small interfering RNAs
(siRNAs) is currently being explored
Treatment of Huntington’s disease contd..

36. 36
Amyotrophic Lateral Sclerosis

37. Amyotrophic Lateral Sclerosis
37
* Amyotrophic Lateral Sclerosis ( Lou Gehrig disease )
* Progressive neurodegenerative disorder of motor neurons
* Muscle wasting & Atrophy
* Characterised by –
 Spontaneous twitching of motor units
 Difficulty in chewing & swallowing
 Respiratory failure leads to death within 2 – 5 years
* Genetic cause is a hexanucleotide repeat expansion in C9ORF72, mutations
in the Cu /Zn SOD1, TARDBP gene encoding TDP-43 and in the FUS/TLS

38. Etiology :
38
 Defect in functioning of SOD (Superoxide dismutase)
 ↓ed uptake of glutamate by glutamate transporters
Overactivity of glutamate at NMDA receptors
Excitotoxicity
Amyotrophic Lateral Sclerosis contd…

39. 39
Treatment :
* Riluzole has both presynaptic and postsynaptic effects
* Inhibits glutamate release, blocks postsynaptic NMDA and kainite type of
glutamate receptors and inhibits voltage dependent Na+ channels
* Dose is 50 mg BD, taken 1 h before or 2 h after a meal
* nausea or diarrhea, hepatic injury (periodic monitoring)
* Edaravone was approved by the FDA for ALS under an orphan drug designation
* Has free radical scavenging properties that may reduce oxidative stress
* It is administered IV, with the first round daily for 14 days, followed by a 14 day
holiday, then in subsequent cycles, 10 out of every 14 days followed by a 14-day
holiday
Amyotrophic Lateral Sclerosis contd…

40. 40
Treatment :
* Baclofen - a GABAb receptor agonist for spasticity in ALS
* Initial doses of 5–10 mg/day, which can be increased to as much as 200 mg/d
* baclofen can be delivered directly into the space around the spinal cord – by
surgically implanted pump and an intrathecal catheter
* Risk of life-threatening CNS depression
* Tizanidine - an agonist of α2 adrenergic receptors in the CNS
* Reduces muscle spasticity, by increasing presynaptic inhibition of motor neurons
* initiated at a low dose of 2–4 mg at bedtime and titrated upward gradually
* Drowsiness, asthenia, and dizziness
Amyotrophic Lateral Sclerosis contd…

41. 41
Multiple sclerosis (MS) :
* Autoimmune demyelinating disorder i.e. inflammation & selective destruction
of central nervous system (CNS) myelin
* Triad of inflammation, demyelination & gliosis (scarring)
* Characterized by weakness, numbness, tingling in limbs, spastic paraparesis,
diplopia & spincture disturbances leading to urinary urgency
* The course can be relapsing-remitting or progressive

42. 42
In relapsing-remitting MS or secondary progressive MS :
* Interferon beta-1b (6 mIU I.M. once a week) has flu-like symptoms, high cost
* Glatiramer acetate – (20mg S.C. daily) synthetic polypeptide resembling myelin
basic protein, S/E – flushing, chest tightness & palpitation
* Dimethyl fumarate – molecule in krebs cycle, modulate expression of
proinflammatory & anti-inflammatory cytokines
* Fingolimod - orally effective immunomodulator, recently approved to treat MS,
supresses release of lymphocytes from lymphoid tissue & protects myelin sheath
Treatment of Multiple sclerosis :

43. 43
Treatment of Multiple sclerosis contd..
* Teriflunomide- inhibit mitochondrial enzyme dihydro-orotate dehydrogenase,
exerts effect by limiting proliferation of rapidly dividing T & B cells
* Natalizumab - monoclonal antibody, blocks process of cell adhesion to
lymphocytes in CNS
* Ocrelizumab – active against CD20 molecule on B-cell precursors
* Alemtuzumab – against CD52 antigen expressed on monocytes & lymphocytes
* Mitoxantrone - anticancer drug recently approved for MS
* Spasticity in MS can be treated using Baclofen or Tizanidine

44. Wilsons disease :
44
* Hepato-lenticular degeneration
* Autosomal recessive disorder caused by mutations in ATP7B gene which encodes
membrane-bound, copper transporting ATPase
* Genetic failure to eliminate copper absorbed from the food - accumulates in brain,
kidney, liver & cornea
* Neurodegeneration and astrogliosis in the basal ganglia, particularly in the
striatum
* Motor disturbances such as tremors, rigidity, dystonia usually manifests in the
second decade may have a history of psychiatric disturbances

45. Treatment of Wilson’s disease :
45
* Aim- reduce tissue copper levels and maintenance therapy to prevent
reaccumulation
* Chelating Agents : D-penicillamine(500mg BD), Trientene (1g/day)
* Decreasing Copper Absorption : Tetrathiomolybdate , Zinc Sulphate
(200mg/day), Potassium disulphide (20mg TDS)
* Trientine and zinc are useful drugs for maintenance therapy
* KF rings tend to decrease after 3–6 months and disappear by 2 years
* With advanced hepatic disease may require a liver transplant & research is
looking into the potential role of organ-specific chelators

46. 46
Prion disease :
* Group of human & animal diseases associated with characteristic type of
neurodegeneration, known as spongiform encephalopathy because of vacuolated
appearance of affected brain
* Bovine spongiform encephalopathy (BSE), is transmissible to humans
* Human forms of spongiform encephalopathy : Creutzfeldt-Jacob disease (CJD)
* Cause progressive, sometimes rapid dementia & loss of motor coordination
* Causes death within 9 months of onset, occurs in age of 50-75 years

47. 47
Treatment of Prion disease :
* No known treatment for this type of encephalopathy
* Quinacrine- can inhibit PrPSc aggregation in mouse models & is under
investigation for treating human CJD
* Pentosan polysulfate - glycosidic polymer that binds PrP & inhibits disease
progression when given by intracerebral injection in animal models, is being
tested in humans
* Anti-PrP antibodies have been shown to prevent prion disease when given
intraperitonally but ineffective when prion inoculated by intracerebral route

48. 48
Conclusion :
 Neurodegenerative disorders are characterized by progressive & irreversible
loss of neurons from specific regions of the brain
 Currently available therapies alleviate disease symptoms only but do not alter
underlying neurodegenerative process
 The available symptomatic treatments for AD, HD, and ALS are much more
limited in effectiveness
 A wide range of disease-modifying approaches hold the promise to transform
approach to both the diagnosis & treatment of neurodegenerative disorders

49. 49
References :
 Harrisons’s principles of internal medicine 20th edition
 The pharmacological basis of therapeutics (Goodman & Gillman) 13th
edition
 General pharmacology-Basic concepts (HL Sharma & KK Sharma) 3nd
edition
 Basic & clinical pharmacology (Katzung) 14th edition
 Rang & Dale’s Pharmacology 7th edition

50. You can insert graphs from Excel or Google Sheets
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