neuroanatomy and the BBB Flashcards
what is the brainstem like and what does it do?
BRAINSTEM (PONS/MEDULLA/MIDBRAIN)
mediates physiological reflexes crucial for survival
baroreceptor reflex maintains blood pressure and heart rate
carbon dioxide sensors maintain breathing
chemoreceptive trigger zone reduces absorption of toxic compounds from the gastro-intestinal tract
Consciousness and sleep
what is the diencephalon composed of and what does it do?
DIENCEPHALON (THALAMUS/HYPOTHALAMUS)
The thalamus has both sensory and motor functions
The hypothalamus controls behaviors crucial for survival (homeostasis)
aggressive, defensive, consumatory, reproductive
controls pituitary hormonal regulation of the body
involved in thermoregulation and control of autonomic nervous system
what does the cerebral cortex do?
CEREBRAL CORTEX
controls sensory and motor activity
responsible for language and concept manipulation
‘generates’ thoughts, ideas, and consciousness
probably stores long term memories
what does the cerbellum do?
CEREBELLUM
Receives inputs from multiple sources
Output primarily to motor areas of cerebral cortex via the thalamus
Coordinates voluntary movement in space and time
Maintains balance
Controls eye movement
Role in motor learning
Alcohol is toxic to cerebellum affecting balance
what is the limbic system like?
LIMBIC SYSTEM
consists of the amygdala, hippocampus, habenula and the septal area
interprets and filters information relayed between the hypothalamus and the cortex
responsible for judgment, evaluation, and the inhibition of the output of inappropriate thoughts, ideas, behaviours, etc.
helps to focus attention by inhibiting irrelevant sensory input and cognitive activity
important in memory formation and emotions
what is the basal ganglia and what does it do?
A group of nuclei forming a functional unit regulating voluntary motor control
Consists of the striatum (caudate-putamen), the globus pallidus, the substantia nigra and the subthalamic nucleus (STN)
Regulates the contraction of opposing muscle bundles allowing smooth and coordinated muscle activity
what can an oligodendrocyte do?
1 oligodendrocyte can myelinate 50 axon segments
microglia and astrocytes are similar
Astrocytes are highly polarized
Astrocytic processes do not overlap
A single astrocyte can ensheath >100,000 synapses
what is the physical blood brain barrier like?
- Physical - tight junctions and membrane layers
Brain capillary endothelial cells lack pores or intercellular clefts (fenestras)
Brain capillary endothelial cells have tight intercellular junctions
Have layers of lipid rich membranes
Brain capillary endothelial cells are surrounded by pericytes and astrocyte end feet which provide extra layers of lipid membranes
what is the chemical description of the BBB like?
- Chemical - – enzymes
Required nutrients cross the BBB by multiple active transport processes
brain capillary endothelial cells have five times more mitochondria
mitochondria have numerous enzymes,
e.g., monoamine oxidase, prevents entry into the brain of neuroactive monoamines in the blood such as noradrenaline, adrenaline, serotonin, and dietary monoamines like tyramine
what is the physiochemical description of the BBB like?
- Physiochemical - plasma protein binding
plasma protein binding keeps neurotoxic lipid soluble compounds such as bilirubin in the blood
Occasionally, bilirubin does get into the brain of neonates producing brain damage and mental retardation known as kernicterus
the cerebral spinal fluid has only 1% as much protein as does the blood (CSF protein binding not very important)
what does the BBB consist of?
The BLOOD BRAIN BARRIER consists of:
Brain capillary endothelial cells with tight junctions
Enzymes of the many endothelial mitochondria
Pericytes and astrocyte end foot processes
Plasma protein binding
why do we need a BBB and what determines passage through the BBB?
Why do we need a BBB?
What determines passage through the BBB?
If they are lipophilic, they diffuse through the lipid layers down their concentration gradient. This is a 2 way street.
If they are not lipophilic, they can be actively carried, but only chemicals that the brain needs are transported into the brain.
Drugs that are transported into the brain: levo-dopa, but this chemical is the precursor of the neurotransmitters dopamine, noradrenaline and adrenaline no others, yet Fat soluble (lipophilic) drugs that get into the brain: Any drug with actions in the brain diazepam, fluoxetine, heroin vs. morphine, ethanol, nicotine, caffeine, cocaine, tetrahydrocannabinol, quetiapine
what are strategies for enhanced CNS drug delivery?
Strategies for enhanced CNS drug delivery:
Drug manipulation
Make drug more lipophilic
Heroin, diacyl derivative of morphine, more lipophilic and so crosses BBB ~100 fold better
Chemical Drug Delivery Systems
Chemical carrier that is lipophilic to cross BBB but converted to hydrophilic form in tissue.Targets the brain specifically
Carrier Mediated Drug Delivery
Large neutral amino acids carrier (LNAA) – levo-dopa
Receptor/Vector Mediated Drug Delivery
Non-transportable drug is conjugated to a protein or receptor-specific monoclonal antibody that undergoes receptor mediated transcytosis through the BBB
Disturbing the BBB
Osmotic disruption using mannitol or arabinose
Biochemical disruption
leukotriene C4 disrupts brain tumor capillaries
Glia induce g-glutamyl transpeptidase in normal brain capillaries
RMP-7 (synthetic bradykinin analog – B2 receptors)
Clinical trial – IV/IA RMP-7 together with carboplatin for treatment of human gliomas
