Neurodegenerative Disorders Pharmacotherapy Dr Jayesh Vaghela

1. PHARMACOTHERAPY
OF
NEURODEGENERATIVE
DISORDERS
Dr. Jayesh Vaghela

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

3. Mechanisms of
Neuronal cell
death
• Protein misfolding &
Aggregation
• Excitotoxicity

4. 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 variants
Can’t find way to its
‘native’
conformation
Nonfunctional,
Mischief in cells

5. Native
protein
External Factors
Misfolded
protein
Oligomer
Insoluble
aggregates
Mutation,
Molecular
chaperones
Cellular disposal
mechanisms
Cellular deposits
Neurotoxicity

7. 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

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

9. Neurodegenerative Diseases Associated With Protein Misfolding And Aggregation
Disease Protein Characteristic pathology Notes
Alzheimer's disease β-Amyloid (Aβ) Amyloid plaques
Aβ 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 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

10. Parkinson’s
disease

11. 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.

12. 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

13. History
Year 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

14. Etiology

15. Genetic factors
• Mutation / over-expression of α-synuclein protein -
autosomal dominant parkinsonism
⇓
• Protein misfolding and Aggregation

16. Oxidative stress
Dopamine
⇓ MAO
DOPAC
⇓
H2O2
⇓ Fe++
Hydroxyl free radicals
⇓ Inadequate protective mechanism
Degeneration of DA neurons

17. 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

18. 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

19. Neurotransmitter Role

20. Corpus
striatum
Glu
DA Glu
GABA
GABA
GABA
Glu
GABA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
Indirect pathway

22. Pathophysiology
Degeneration of darkly
pigmented
dopaminergic neurons
in SN
Loss of Dopamine
in neostriatum
Lewy bodies
(Intracellular
inclusion bodies)

23. Clinical Manifestations

24. Cardinal features
Bradykinesia
Rigidity Tremor
Other motor features Non-motor features
Gait disturbance
Anosmia
‘Shuffling gait’
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

25. Pharmacotherapy

26. • 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

27. 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

28.  Drugs affecting brain Cholinergic system :
(a) Central anticholinergics: - Trihexyphenidyl (Benzhexole),
- Benztropine mesylate,
- Procyclidine,
- Biperiden
(b) Antihistaminics : - Diphenhydramine

29. 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

30. 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

31.  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

32.  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

33. Contraindications
• Psychoses
• Narrow angle glaucoma
• Cardiac arrhythmias
• Melanoma (∵ levodopa is precursor of skin melanin)

34. 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

35. Blood Brain Barrier
L-dopa
DDC
MAO-B Dopamine
DOPAC
DA
D2
3-o-methyl dopa
3-o-methyl dopa
(Competes with l-dopa
for uptake)
COMT
Levodopa
DDC Carbidopa
Dopamine
Does not cross BBB
Peripheral degradation
ADRs
Brain
Peripheral tissue, Gut

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. • Desmethyl selegiline (metabolite) is responsible for
neuroprotection & antiapoptotic effect
• ADR : - Insomnia
• Dose : - 5 mg with breakfast
- 5 mg with lunch

45. 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

46. • 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

47. 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

48.  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)

49. Blood Brain Barrier
L-dopa
DDC
MAO-B Dopamine
DOPAC
DA
D2
3-o-methyl dopa
3-o-methyl dopa
(Competes with l-dopa
for uptake)
Entacapone
Tolcapone
COMT
Levodopa
DDC Carbidopa
Dopamine
Does not cross BBB
Peripheral degradation
ADRs
Brain
Peripheral tissue, Gut
Selegiline
Tolcapone
Amantadine
Bromocriptine

50. Other supportive drugs
• Depression- Citalopram (or Amitriptyline)
• Dementia in ~30% with late disease
• Treat as per dementia guideline
• Psychosis-low dose Clozapine or Quetiapine

51. 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

52. Other DOPAMINE AGONIST :
• Sumanirole – also neuroprotective

53. 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

54. OTHER SURGICAL PROCEDURES
 ABLATIVE
• Thalamotomy,
• Pallidotomy
 RESTORATIVE –
• Embryonic dopaminergic tissue transplantation

55. ADVERSE EFFECTS
• Hemorrhage,
• Infection,
• Wire breakage,
• Speech impairment,
• Dystonia

56. 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

57. BOTULINUM TOXIN
• In patients dystonias it is very beneficial and the results
last for 3 to 4 months.
• Blepharospasm has always responded

58. 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.

59. 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.

60. • 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

61. 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.

63. PHARMACOTHERAPY OF
NEURODEGENERATIVE
DISORDERS
Part – 2
Dr. Jayesh Vaghela

64. Overview
• Alzheimer’s disease (AD)
• Huntington’s disease (HD)
• Amyotrophic Lateral Sclerosis (ALS)

65. 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

66. The Stages of Alzheimer’s Disease
Mild Moderate Severe
Memory
Loss
Language
Problems
Mood and
Personality
Changes
Diminished
Judgement
Behavioral, Personality
Changes
Unable to Learn or
Recall New
Information
Long-Term Memory
Affected
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

67. STAGES OF AD

68. Neuropathology
• Loss of neurons and synapses in the cerebral cortex and
certain subcortical regions.

69.  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

70. 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

71. Amyloid
Hypothesis

75. ‘Tau’
Hypothesis

76. 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)

78. Pharmacotherapy

79. 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 AD
Mild–moderate
AD,
Mild–moderate
AD
Mild–moderate
AD
Metabolism
CYP2D6,
CYP3A4
Esterases
CYP2D6,
CYP3A4
CYP1A2

80. Recent Advances
in treatment of
AD

81. 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

82. • 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

83. β-secretase inhibitors
(β-site APP cleaving enzyme, BACE1)
GSK188909
non-peptidic BACE1
inhibitor
oral
Significant reduction in the
level of Aβ40 and Aβ42 in
the brain
PMS777
Cholinesterase
inhibitor with anti-
PAF activity
Decrease sAPPα secretion
and Aβ42 release

84. γ-secretase inhibitors/modulators
DAPT,
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
controlled
Phase III study
no benefit on cognitive
or functional outcomes,
discontinued

85. 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

86. α-secretase activators/modulators
ADAM 10
ADAM 17
ADAM 9
Adamalysin
family 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
by
promoting ADAM10 and
PKCα/ε translocation
Neuroprotective agent

87. 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

88. M1 muscarinic agonists
Talsaclidine
Selective
muscarinic
M1
agonist
Stimulates non-amyloidogenic
α-secretase
processing in
vitro
Decreased CSF Aβ by
about 20%
AF102B M1 agonist
Decreased CSF Aβ
of AD patients
AF267B In clinical trials

89. Aβ-aggregation inhibitors
iAβ5p β-sheet breaker
Intrahippocampal
injection improved
spatial memory and
decreased amyloid
plaque deposits

90. Immunotherapy
New modified
vaccines
Novel peptide-carrier
protein using an
amino terminal
fragment of Aβ are
under development
to avoid potentially
harmful T-cell
responses
Maintain a similar
antibody response to
that of
AN1792

91. LY2062430
IVIG
against Aβ
peptide
Phase II trials
Decreased
cognitive
Decline
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

92. 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

93. 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

94. Alzheimer’s Disease
⇓
↑ RAGE and ↓ LRP-1
⇓
Inhibition of RAGE &
Activation of LRP-1
⇓
Therapeutic Targets

95. 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 decreased
CSF Aβ42 compared with
placebo
But not plasma Aβ

96. 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

97. Monoamine oxidase inhibitors
Rasagiline MAO-B inhibitor
Regulation of APP processing,
Inhibition of cell death markers and
upregulation of neurotrophic factors
Ladostigil
Dual AchE & BuChE
And
Brain selective
MAO-A and -B
inhibitor
Regulate APP processing

98. Treatments based on tau pathology
Lithium,
AF267B,
Propentofylline (PPF),
SRN-003 & 556
Prevented the
hyperphosphorylation of tau
Phenothiazines
Anthraquinones
Polyphenols
Thiocarbocyanine dyes
N-Phenylamines,
Thiazolyl-hydrazides,
Rhodanines,
Quinoxalines,
Aminothienopyridazines
Prevent tau protein
aggregation

99. Targeting tau
chaperones
Prevent the
misfolding of tau
Phosphorylated tau
antigens
Reduction in soluble
and insoluble
phosphorylated tau
Significant
attenuation of
cognitive
impairment

100. 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

101. 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

102. 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

103. 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

104. 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

105. • 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

106. 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

107. 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

108. 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

109. 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

110. Huntington’s
Disease

111. 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

113. 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

114. 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

116. 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

117. Etiopathogenesis
Genetic error in HUNTINGTIN GENE
⇓
Abnormal synthesis of Huntingtin protein
(Several repeats of polyglutamine)
⇓
Neuronal loss in striatum & cortex
⇓
Involuntary jerky movements

118. Corpus
striatum
Glu
DA Glu
GABA
GABA
GABA
Glu
GABA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
HD
Indirect pathway

119. 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

120. Clinical Features
• Impaired intellectual functioning
• Interfere with normal activities
• Less ability to solve the problems
• Agitation and sleeping disturbance.
• Progressive mental deterioration

121. 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

122. 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

123. Drugs
Drug Mechanism Dose ADRs
Chlorpromazine 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

124. Amyotrophic
Lateral
Sclerosis
(ALS)
Lou Gehrig disease

125. 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

126. Etiology
 Defect in functioning of SOD (Superoxide dismutase)
 ↓ed uptake of glutamate by glutamate transporters
⇓
Overactivity of glutamate at NMDA receptors
⇓
Excitotoxicity

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

128. 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

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

130. Other drugs
 Gabapentin:
• Slows decline in muscle strength
 Ceftriaxone:
• 3rd generation cephalosporin
• ↑es glutamate uptake
• Anti excitotoxic

131. “Ice-Bucket
Challenge”
 Raising awareness
about ALS
 Accept the
challenge or
Donate or do both

132. 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.

133. Thank You