Transcript Downloadable Powerpoint File ()

NeurodexTM Palliates Pseudobulbar Affect:
An Overview of the Pathogenesis of Pseudobulbar Affect
and the Pharmacologic Mechanism of Action of Neurodex
Ursula Hess, PhD
Torre Lazur McCann West
Neural Circuits Hypothesized to Mediate
Emotional Motor Expression
• Cortico-Bulbar Circuit
Cortex controls bulbar-generated
laughing/crying and inhibits
involuntary affective motor displays
• Cortico-Pontine-Cerebellar Circuit
Cerebellum communicates with
cortical association areas and
adjusts laughing/crying responses to
appropriate cognitive/social context
Monoamine Centers in Brainstem Regulate
Networks That Mediate Emotional Motor Expression
• Brainstem monoamine (5-HT, NE, DA)
centers send diffuse projections
throughout the brain
• Monoamines are neuromodulators
and may cause physiological state changes
that raise or lower the threshold of activation
of neural networks that trigger emotional expression
Brain Pathways Commonly Damaged
in PBA Patients
Disconnection Hypothesis
Lesions of cortico-bulbar tracts may
release bulbar-generated laughing/crying
from cortical control
Cerebellar Hypothesis
Lesions that interrupt cerebellar
communication with cortex or
effector regions may disrupt
adjustment of emotional responses
to context
Monoamine Hypothesis
Damage to monoamine centers or their
ascending projections is proposed to correlate
with PBA severity. Dysfunction of modulatory paths
may lower the threshold for laughing/crying
DM Primarily Targets Brain Regions
Believed to Mediate Emotional Motor Expression
and Modulates NT Systems Implicated in PBA
DM 1o Targets Brainstem and Cerebellum
Likely Due to Its Sigma Properties
• Sigma 1 agonist
DM Modulates Glutamatergic and
Monoaminergic Signaling
• Decreases excitatory Glu signaling
(NMDA antagonist, sigma 1 agonist)
• DM modulates DA and 5-HT release
in some brain systems
DM may palliate PBA via
1) Targeted action on sigma Rs in brainstem
2) Distributed action on monoamine systems
that raises threshold of laughing/crying
Brain Circuits Mediating Laughing and Crying
A SIMPLE HYPOTHESIS
• Motor cortex pyramidal neurons control
bulbar motor neurons that mediate
facio-respiratory functions associated
with laughing/crying
— Direct cortical signals are
Excitatory, Glu+
• Monoamine centers in brainstem can modulate
facio-respiratory functions by raising/lowering
threshold at which cortical neurons can evoke
brainstem motor neuron responses
— Monoamines set
Inhibitory (-) Tone
Brain Pathology That Disturbs
Integrity of These Circuits May Result in PBA
A SIMPLE HYPOTHESIS
• Damage to cortico-bulbar or
cerebellar-motor cortex paths results in
Excess Cortical Excitation (Glu+)
of bulbar motor neurons and triggers
involuntary laughing/crying
• Damage to brainstem monoamine centers or
their ascending/descending tracts
Decreases Inhibitory (-) Tone
on cortico-bulbar circuits and
lowers threshold for laughing/crying
Sigma Modulation of Excitatory Neurotransmission
Excitatory Cortico-Bulbar Synapse
• Neurotransmitter: Glutamate (Glu
)
• Glu Receptors: NMDA and AMPA
• Influx of Na+ and Ca2+ excites neuron
• Presynaptic sigma 1 Rs may modulate
Glu release via effects on Ca2+ flux
• Postsynaptic sigma 1 Rs may indirectly
modulate NMDA responses, via effects
on intracellular Ca2+ homeostasis
DM May Decrease Excess BS Motor Neuron Excitation
and Raise Low Threshold for Laughing/Crying
• Targeted, concerted action to decrease
cortico-bulbar excitatory signaling
— DM inhibits Glu release via sigma activity
— DM weakly blocks NMDA responses
• Diffuse, indirect action to raise low threshold
for laughing/crying
— DM may increase inhibitory tone
Neuropharmacology of DM
• Sigma 1 R agonist
• Weak, noncompetitive NMDA R antagonist that binds PCP site
• Decreases K+-stimulated glutamate release
• Reduces KCl and NMDA-induced increases in intracellular Ca2+
concentration via voltage- and receptor-gated Ca2+ channels
• Noncompetitive a3b4 nicotinic R antagonist; thereby proposed
to modulate DA release in the mesolimbic pathway
• Increases 5-HT release in the brainstem
nucleus of the solitary tract (NTS)