PHAR 562
Neurodegeneration – Motor neuron disease
Vocab
Motor neuron disease
- Impairment in muscle innervation
Spinal Muscular Atrophy
- Early impairment of muscle innervation
Ataxia
- Loss of voluntary movement
Dementia
- Memory and cognitive functions impairment
o AD
o Vascular Dementia
o PD
o HD
o Lewy body dementia
o Trisomy 21
Multiple sclerosis
- Degeneration of myelin sheaths
Anatomy
- Motor unit => basic unit of motor function
o A motor neuron and the group of muscle fibers it innervates
- Upper and lower motor neurons
o Upper
Derive from motor cortex / brain stem
Project to lower motor neurons
Release glutamate on the lower motor neurons as means of
communication
o Lower
Located in spinal cord
Innervate muscles and mediates voluntary movement
Exception cranial nerve is the lower motor neuron with nuclei
located in brainstem as it innervates tongue and eyes
- Motor Neuron Diseases
o Occur when motor neurons become damaged
o Present as muscle weakness
Muscles are less innervated => loss of control
May lead to difficulty breathing & swallowing
o UMN diseases may present differently from LMN diseases
Amyotrophic lateral sclerosis (ALS)
UMN and LMN are both affected
,PHAR 562
Most common motor neuron disease
Dysmorphic disease – weakness that spreads
Diverse pathology
Primary Lateral Sclerosis (PLS)
UMN affected
Progressive Muscular Atrophy (PMA)
LMN affected
- Diagnosis
o UMN (upper motor neurons) signs
Babinski sign – upward response of big toe when stimulated
Hyperreflexia – hyperactive repeating reflexes
Spasticity
o LMN
Muscle atrophy and weakness
Fasciculations (looks like spasms but it is constant)
Decreased muscle tone
Hyporeflexia
o Difficulty diagnosing ALS as there could be both hyperreflexia (UMN) and
hyporeflexia (LMN) – symptoms may mask each other
Amyotrophic Lateral Sclerosis (ALS) – AKA Lou Gehring’s disease or Charcot’s disease
- Amyotrophy => neurogenic atrophy of the muscle
- Lateral sclerosis => hardness of the spinal cord seen when ALS patients are examined at
autopsy
o Caused by the proliferation of astrocytes and scars
- Forms of ALS:
o Classical sporadic
o Familial
o Geographic variant
- Age onset 55-65
o Can start at 45
- Seen in 1-2/100,000 – affecting more males
- 50% patients die within 3 years of onset, 90% die within 5 years
- Usually starts in the limbs, can be very heterogenous
o Can start in face too
- 30% bulbar (medulla oblongata) onset => tongue affected first
o Patients have issues with speech and swallowing
- All muscles are affected in ALS except ocular and bladder
- Respiratory problems are the major discomfort and major cause of death
- Interventions:
o No treatment
o End stage: Breathing tube or non-invasive mechanical ventilation (not easily
accessible since patients are often not mobile)
, PHAR 562
o Pharmacological treatment Riluzole
Increased life expectancy by a few months
Suggested Disease Mechanism 1: Dying forward hypothesis
Cortical dysfunction and hyperexcitability
- Trans-synaptic glutamatergic excitotoxicity
o Something happens in the cortex triggers the hyperexcitability of motor neurons
leading to increased glutamate in the synaptic cleft leading to toxicity of lower
motor neurons (Dying forward hypothesis)
o Glutamate in the synaptic cleft is normally cleared by pre- and post-synaptic
terminals & by astrocytes that express EAAT2 (Excitatory amino acid transporter 2)
on the surface
EAAT2
Glutamate transporter on astrocytes that clear away glutamate
from synaptic cleft
Decreased in ALS
- Hyperexcitability via NDMAR and AMPAR
o GluR2 deficiency occurs in some ALS patients
It is required for Ca2+ entry into the cell
o Swelling of motor neurons observed due to an increased Na+ and Cl-, leading to
accumulation of water
- Riluzole
o Reduces cortical hyperexcitability and blocks glutamatergic neurotransmission
through 7 different mechanisms
Glutamate release from presynaptic terminal inhibited by blocking Na+
and Ca2+ channels (1-2)
Blocks NMDAR, AMPAR, and Kainate receptors in the postsynaptic
terminal, so that there is less Ca2+ influx (3,4,5)
Potentiates glutamate uptake by astrocytes via EAAT2 (6)
Inhibits glutamate release (7)
o Mechanism indicates dying forward mechanism is involved in ALS
Heterogenous presentation of disease indicates that other mechanisms
may be involved too
- Pharmacology of Riluzole
o ADME
Absorption: 50mg BID; Bioavailability: 60% oral
Distribution: 96% bound to plasma protein (increasing its half-life)
Metabolism: CYP1A2 hydroxylation
Drug-drug interaction with other CYP1A2 substrates (e.g.,
acetaminophen, caffeine, warfarin)
Excretion: 95% renal as glucoronides
o Adverse events: Blurred vision, difficulty breathing, weakness, dizziness, GI
discomfort
Neurodegeneration – Motor neuron disease
Vocab
Motor neuron disease
- Impairment in muscle innervation
Spinal Muscular Atrophy
- Early impairment of muscle innervation
Ataxia
- Loss of voluntary movement
Dementia
- Memory and cognitive functions impairment
o AD
o Vascular Dementia
o PD
o HD
o Lewy body dementia
o Trisomy 21
Multiple sclerosis
- Degeneration of myelin sheaths
Anatomy
- Motor unit => basic unit of motor function
o A motor neuron and the group of muscle fibers it innervates
- Upper and lower motor neurons
o Upper
Derive from motor cortex / brain stem
Project to lower motor neurons
Release glutamate on the lower motor neurons as means of
communication
o Lower
Located in spinal cord
Innervate muscles and mediates voluntary movement
Exception cranial nerve is the lower motor neuron with nuclei
located in brainstem as it innervates tongue and eyes
- Motor Neuron Diseases
o Occur when motor neurons become damaged
o Present as muscle weakness
Muscles are less innervated => loss of control
May lead to difficulty breathing & swallowing
o UMN diseases may present differently from LMN diseases
Amyotrophic lateral sclerosis (ALS)
UMN and LMN are both affected
,PHAR 562
Most common motor neuron disease
Dysmorphic disease – weakness that spreads
Diverse pathology
Primary Lateral Sclerosis (PLS)
UMN affected
Progressive Muscular Atrophy (PMA)
LMN affected
- Diagnosis
o UMN (upper motor neurons) signs
Babinski sign – upward response of big toe when stimulated
Hyperreflexia – hyperactive repeating reflexes
Spasticity
o LMN
Muscle atrophy and weakness
Fasciculations (looks like spasms but it is constant)
Decreased muscle tone
Hyporeflexia
o Difficulty diagnosing ALS as there could be both hyperreflexia (UMN) and
hyporeflexia (LMN) – symptoms may mask each other
Amyotrophic Lateral Sclerosis (ALS) – AKA Lou Gehring’s disease or Charcot’s disease
- Amyotrophy => neurogenic atrophy of the muscle
- Lateral sclerosis => hardness of the spinal cord seen when ALS patients are examined at
autopsy
o Caused by the proliferation of astrocytes and scars
- Forms of ALS:
o Classical sporadic
o Familial
o Geographic variant
- Age onset 55-65
o Can start at 45
- Seen in 1-2/100,000 – affecting more males
- 50% patients die within 3 years of onset, 90% die within 5 years
- Usually starts in the limbs, can be very heterogenous
o Can start in face too
- 30% bulbar (medulla oblongata) onset => tongue affected first
o Patients have issues with speech and swallowing
- All muscles are affected in ALS except ocular and bladder
- Respiratory problems are the major discomfort and major cause of death
- Interventions:
o No treatment
o End stage: Breathing tube or non-invasive mechanical ventilation (not easily
accessible since patients are often not mobile)
, PHAR 562
o Pharmacological treatment Riluzole
Increased life expectancy by a few months
Suggested Disease Mechanism 1: Dying forward hypothesis
Cortical dysfunction and hyperexcitability
- Trans-synaptic glutamatergic excitotoxicity
o Something happens in the cortex triggers the hyperexcitability of motor neurons
leading to increased glutamate in the synaptic cleft leading to toxicity of lower
motor neurons (Dying forward hypothesis)
o Glutamate in the synaptic cleft is normally cleared by pre- and post-synaptic
terminals & by astrocytes that express EAAT2 (Excitatory amino acid transporter 2)
on the surface
EAAT2
Glutamate transporter on astrocytes that clear away glutamate
from synaptic cleft
Decreased in ALS
- Hyperexcitability via NDMAR and AMPAR
o GluR2 deficiency occurs in some ALS patients
It is required for Ca2+ entry into the cell
o Swelling of motor neurons observed due to an increased Na+ and Cl-, leading to
accumulation of water
- Riluzole
o Reduces cortical hyperexcitability and blocks glutamatergic neurotransmission
through 7 different mechanisms
Glutamate release from presynaptic terminal inhibited by blocking Na+
and Ca2+ channels (1-2)
Blocks NMDAR, AMPAR, and Kainate receptors in the postsynaptic
terminal, so that there is less Ca2+ influx (3,4,5)
Potentiates glutamate uptake by astrocytes via EAAT2 (6)
Inhibits glutamate release (7)
o Mechanism indicates dying forward mechanism is involved in ALS
Heterogenous presentation of disease indicates that other mechanisms
may be involved too
- Pharmacology of Riluzole
o ADME
Absorption: 50mg BID; Bioavailability: 60% oral
Distribution: 96% bound to plasma protein (increasing its half-life)
Metabolism: CYP1A2 hydroxylation
Drug-drug interaction with other CYP1A2 substrates (e.g.,
acetaminophen, caffeine, warfarin)
Excretion: 95% renal as glucoronides
o Adverse events: Blurred vision, difficulty breathing, weakness, dizziness, GI
discomfort
