Accutane prescription drug pill used to treat cystic acne

1

• Accutane prescription drug (pill) used to treat
  cystic acne
• a synthetic Vitamin A (a retinoic acid)
• isotretinoin

2

• Accutane interferes with the development of
• Central Nervous System
• Craniofacial structures
• The Heart
• The Thymus and Parathyroid Glands
• Other organ systems

3

• Embryonic Exposure to Accutane (Isotretinoin)
• Spontaneous Abortion (40)
• Major Malformations (35)
• Prematurity 16

4
(No Transcript)
5
(No Transcript)
6

• CNS Abnormalities
• Cerebellar Hypoplasia (small cerebellum)
• Absence or Reduced Size of the Cerebellar
  Vermis (a part of the cerebellum)
• Ventriculomegaly (4th) enlargement of the 4th
  ventricle
• Cranial Nerve Abnormalities (optic oculomotor)

7

• Additional CNS Abnormalities (visible on
  autopsy Lammer and Armstrong, 1991)
• Pons
• Medulla
• Thalamus
• Hippocampus
• Heterotopias in Frontal Cortex
• reduced myelination

8
Figure 1. Mental ability of children exposed to
isotretinoin during embryonic development.
9

• Is vulnerability to the CNS effects of retinoic
  acid seen in adolescence?
• controversial human data suggest that some
  individuals of unspecified ages may experience
  depression, suicidality, or psychosis following
  Accutane treatment (Wysowski, Pitts, and Beitz,
  2001 Bremner, 2003)
• long term effects are unknown
• 2 studies in adolescent mice show that 21 days
  of treatment with 1 mg/kg/day 13 cis RA reduces
  hippocampal cell survival (Sakai et al, 2004) and
  reduces spatial learning (Crandall et al, 2004)
• reduced hippocampal neurogenesis has been shown
  in depression (increased during antidepressant
  treatment)

10

• Glutamate
• A. General functions in brain
  (non-neurotransmitter functions)
• - important metabolic role
• - detoxifies ammonia in brain
• - building block in synthesis of proteins and
  peptides
• - precursor for GABA

11
B. Synthesis and metabolism - made in axon
terminals from glucose (coming from cell
metabolism) and from glutamine (coming from glial
cells) - glutaminase is the enzyme that converts
above to glutamate (Glutamic acid) - stored in
vesicles and released by Calcium dependent
exocytosis - action terminated by high affinity
reuptake transporter on presynaptic neuron and
glial cells (also helps to maintain extracellular
GLU below levels that may damage neurons) -
extracellular enzymes not relevant to termination
of action
12
C. Receptors 5 types responsible for most
excitatory transmission in the CNS 1. NMDA
receptors ionotropic, but slow excitatory
longterm potentiation and memory formation,
developmental plasticity, epilepsy, neurotoxicity
related to brain damage 2. kainate receptors -
ionotropic, excitatory 3. AMPA receptors -
ionotropic, excitatory 4. AP4 receptors
(inhibitory autoreceptor) 5. ACPD receptors
slow, second messenger action that modifies
inositol phosphate metabolism Individual
synapses that use GLU appear to use combinations
of these receptors, rather than a distinct type.
13
D. The NMDA receptor complex Found throughout
brain and spinal cord, particularly dense in
hippocampus and cerebral cortex A
voltage-dependent Mg blockade important in
modulating receptor action Role in longterm
potentiation and memory formation, developmental
plasticity, epilepsy, neurotoxicity related to
brain damage - overactivation of NMDA
receptors can damage and/or kill neurons via
excitotoxicity