A detailed material on Alzheimer disease, Parkinson disease, parkinsonism, multiple sclerosis, huntingtons disease, wilsons disease, amyotrophic lateral sclerosis

1. DR. SIDDHARTHA DUTTA
MAMC, NEW DELHI

2. Introduction
NDD
Current therapy
Recent advances in
pharmacotherapy
Summary

3.  Neurodegenerative diseases are a heterogeneous
group of disorders that are characterized by the
progressive degeneration of the structure and
function of the central nervous system
or peripheral nervous system
 Incurable and leads to debilitating conditions
 Cognitive disability, Ataxia and dementia

4. Alzheimer's disease (AD
Parkinson's disease (PD)
Multiple sclerosis (MS)
Wilson’s disease(WD)
Amyotrophic lateral sclerosis (ALS)
Huntington's disease (HD)

5.  Alzheimer’s disease(AD) is a chronic neurodegenerative
disease(NDD) that an include progressive memory loss
and difficulties with thinking, problem-solving or
language
 Dr. Alois Alzhiemers
 60% to 70% of cases of dementia
 4th leading cause of death
 44 million people affected worldwide , 4.1 million in

6.  Medial temporal lobe,
entorhinal cortex,
hippocampus
 Anterograde memory loss
 Current diagnostic criteria for AD
require the presence of dementia
(cognitive impairments sufficient to reduce function)
 Mild cognitive impairment (MCI)
 MCI progress at a rate of about 10% per year to AD
 Later stages - akinetic-mute state

7.  GENETICS- APP, PSEN1, PSEN2 [AD TYPE]
 Tau hyperphosphorylation
 Cholinergic insufficiency
 APOE- lipid carrier protein apoE, E4 allele – 3x risk
 PPAR receptors- key role in Aβ clearance
 Hormonal- Insulin resistance, ↓Estrogen, ↓ NGF
 Induce neuronal dysfunction and death by direct impairment
of synaptic transmission, oxidative stress and neuro-
inflammation

10. CHOLINERGIC
HYPOTHESIS

11. Atrophy and degeneration of subcortical
cholinergic neurons
Basal Forebrain
(Nucleus basalis of Meynert)
Provide cholinergic innervation to the
cerebral cortex

12.  Cholinesterase inhibitors
Donepezil, Galantamine, Rivastigmine & Tacrine
 NMDA type glutamate receptor antagonist- Memantine
 Piracetam : GABA derivative has no GABA like activity. It
selectively improves efficiency of higher telencephalic neurons
 Citicoline: Derived from choline and cytidine, involved in
biosynthesis of lecithin
 Improve cerebral function by increasing blood flow to the brain and
enhancing cerebral metabolism
 Antioxidant therapies??

13. 1. Secretase inhibitors
2. Immunotherapy
3. Neprilysin
4. Altering BBB transport
5. Inhibition of Aβ aggregation
6. Antioxidants
7. Statins
8. Dimebon
9. Estrogens

14. DRUG PHASE MOA FEATURES
Semagacestat Phase 3 γ secretase
inhibitor
Dose dependent dec in amyloid
in CSF, plasma and brain
Tarenflurbil Phase 2 γ secretase
inhibitor
NSAIDS enantiomer of
flurbiprofen
Mild to moderate AD
Safe and well tolerated
Showed possible benefit
Talsaclidine Phase 2 Activates α
secretase and
inhibits γ
secretase
Non-selective muscarinic
agonist
Full agonist at the M 1,
Partial agonist at the M2 and
M3
Dose-limiting side effects

15. DRUG PHAS
E
MOA FEATURES
Solanezumab 3 humanized monoclonal IgG1
antibody directed against the
mid-domain of the Aβ peptide
Dose dependent change
Change in cognitive
scores not noted
Bapineuzumab 3 humanized form of murine
monoclonal antibody 3D6,
which targets the N-terminal
region of Aβ
safe and well-tolerated
new microhemorrhage
at highest dose
AN- 1792
(suspended)
2 synthetic full-length
Aβ peptide with QS-21
adjuvant.
induce an immune response
that would remove brain
amyloid deposition
aseptic
meningoencephalitis.

16.  Phenserine: Phenserine treatments increased cognition and
regional cerebral metabolic rate for glucose in AD patients
 Dimebon: A cholinesterase inhibitor and also a NMDA-
antagonist, showed improved cognitive and self-service
functions while diminishing the psychopathic symptoms in
AD patients
 Stopped during phase 3
 Huperzine A: A Chinese herb with reversibly and selectively
acetylcholinesterase inhibition activity

17. Neprilysin (NEP)
Insulin degrading enzyme (IDE)
Plasmin
Endothelin converting enzyme (ECE)
Angiotensin-converting enzyme

18. The receptor for advanced glycation end products (RAGE)
resides in the blood vessel wall cells and transport Aβ across
the blood brain barrier from systemic circulation to facilitate
their accumulation in brain
In contrast to RAGE, low-density lipoprotein receptor-
related protein-1 (LRP-1) mediates transport of Aβ peptide
out of brain.
Thus inhibition of RAGE and/or activation of LRP-1 can
have a therapeutic potential
PF-04494700 oral antagonist (phase 2)

19. There is increasing evidence that metal (mainly Cu, Zn and
Fe) metabolism is involved in the major pathophysiological
events of AD: APP processing and tau hyperphosphorylation
Several chelators of Zn/Cu have been shown to inhibit Aβ
aggregation in vitro and in vivo
A phase II clinical trial with clioquinol, a metal-protein-
attenuating compound that inhibits zinc and copper ions from
binding to Aβ, led to improved cognition

20.  Ladostigil : A multimodal drug, combined
neuroprotective effects with monoamine oxidase (MAO) -
A and -B and cholinesterase inhibitory activities in a
single molecule, was tested and now in Phase II clinical
trial.
 PMS777: A new cholinesterase inhibitor with anti-PAF
activity is also in clinical trial

21.  Imatinib: A tyrosine kinase inhibitor, cause increase of NEP
protein, mRNA
levels, and activity.
 Valproic acid: A widely used drug in the treatment of epilepsy,
was capable
of up-regulating NEP expression, seen in experimental rats.
 Estrogen and green tea all could increase NEP activity and
suggest their potential in AD treatment but there is a long
way before their final clinical application.

22. 1. RESVERATROL
2. DOCOSA-HEXAENOIC ACID
(DHA)
3. GREEN TEA
4. VIT E
5. GINKGO BILOBA
6. GINSENG
7. CURCUMIN

24. Parkinson’s disease is a clinical syndrome consisting of four
cardinal features:
 Bradykinesia
 Muscular rigidity
 Resting tremor
 Postural instability

25.  Dopamine precursor : Levodopa
 Peripheral decarboxylase inhibitors: Carbidopa, Benserazide
 Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole,
Apomorphine
 MAO-B inhibitor: Selegiline, Rasagiline
 COMT inhibitors: Entacapone, Tolcapone
 Dopamine facilitator: Amantadine

31. Autoimmune disease resulting in demyelination of neurons
Frequency of relapses can be decreased by beta-interferon or
glatiramer (resembles myelin basic protein) in relapsing
remitting MS
Spasticity can be decreased by baclofen or tizanidine
Dalfampridine is an oral K+ channel blocker indicated to
improve walking in patients with multiple sclerosis
Modafinil is approved for improving fatigue in multiple sclerosis

32. Drug Mechanism Route
Frequency
ADR
Interferon-β
1a
• Downregulates
expression of MHC on
APC
• ↓ proinflammatory & ↑
regulatory cytokines
• ↓ T cell proliferation
• ↓ entry of inflammatory
cells to CNS
IM
Once a week
• Flu like
syndrome
• LFT
alteration
• Inj site
reaction
• Neutralizing
antibody
Interferon-β
1b
SC
Thrice a week
Glatiramer • ↑ suppressor T cells
• ↓ proinflammatory & ↑
regulatory cytokines
• Displaces MBP by
20 mg SC
daily
• Flushing
• palpitation

33. Drug Mechanism Route
Frequency
ADR
Natalizumab
(Mab against a4
subunit of a4b1
integrin on
lymphocytes)
Prevents lymphocytes
from binding to endothelial
cells, thus inhibits transfer
across BBB and entry in
CNS
I.V.
infusion
Once a
month
PML
if used for
>2years
Fingolimod • Traps lymphocytes
in spleen and lymph nodes
by preventing their
entry in CNS decreases
0.5-1.25 mg
Oral
Once a day
• Altered LFT
• First degree
heart block
• Bradycardia
Mitoxantrone
(Anthracycline)
Topoisomerase II
inhibition- suppress B,T cells
& M attack on myelin
I.V. Once in 3
months
Cardiotoxicity
• Acute leukemia
Dimethyl
fumarate
Promotes anti inflammatory
and inhibit pro-inflammatory
cytokines
Oral Twice a
day
PML
Teriflnomide DHODH inhibitor Oral Once a
day
Hepatotoxicity
Cladribine Inhibit DNA
synthesis and
repair
Oral Used for
2
weeks every
Immunosuppression
• 2ͦ̊˚ neoplasms
• Herpes zoster

35.  Hepatolenticular degeneration due to excessive accumulation of
copper
 Trientine -copper chelating agent with much less toxicity.
 Zinc sulphate and potassium sulfide decrease intestinal absorption
of copper and induce hepatic metallothinein synthesis, that
sequester additional toxic copper
 Zinc sulphate can be used for maintenance therapy and is much
safer than other drugs
Wilson disease Drug of choice
Hepatitis or cirrhosis without decompensation Zinc
Mild to moderate hepatic decompensation Trientine + zinc
Neurological or psychiatric symptoms Tetrathiomolybdate +
zinc
For maintenance, children, pregnancy Zinc

36. AMYOTROPHIC LATERAL
SCLEROSIS
Degeneration of neurons in spinal cord, medulla or
cortex
Spasticity is the major presenting feature
Riluzole is an NMDA antagonist that is useful in
ALS
Most useful agent for symptomatic treatment of
spasticity in ALS is baclofen

37.  Loss of GABAergic neurons in the striatum that lead to
dopaminergic overactivity(opposite to Parkinsonism)
 D2 blockers like chlorpromazine, haloperidol as well as
olanzapine are useful in the treatment of this disease
 Tetrabenazine (dopamine depleter) has been recently
approved for this indication
 Reserpine also act by depleting central monoamines