Peptide Delivery To The CNS Flashcards

0
Q

What is the main circulation route of CSF?

A

Through lateral, third and fourth ventricles

Down around the spinal cord and up through the surface of the brain

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1
Q

What is cerebrospinal fluid?

A

Blood borne fluid produced in the brain and circulates throughout the brain and spinal cord. It is then absorbed back to the blood circulations

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2
Q

What is pervascular circulation?

A

Where a portion (5%) of the CSF flows along the perivascular space and extends from the sub-arachnoid space through the brain parenchyma

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3
Q

Where is CSF absorbed back into?

A

The superior sagittal sinus and other venous structures through arachiod granulation a

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4
Q

What is the function of the CSF?

A
  • supports the brain

- transports nutrients, chemical messengers and waste in and out of the brain

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5
Q

What is the CSF turnover rate?

A

About 8 hours in humans (1 hour in rats)

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6
Q

How do the components of the CSF differ from plasma?

A
  • protein content in CSF is 100x less than plasma
  • plasma contains 50-79g/L of proteins, while CSF only contains 0.5g/L
  • CSF contains approximate 0.3% of plasma proteins
  • drug metabolism is different from that in plasma
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7
Q

What are the brain barriers?

A

The structures and functions that

  • isolate the CNS from the general circulation
  • separate the brain parenchyma from the CSF circulation
  1. Blood brain barrier
  2. Blood CSF barrier
  3. CSF brain barrier
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8
Q

What is the blood brain barrier comprised of?

A
  • endothelial cells packed tightly in brain capillaries that more greatly restrict passage of substances from the bloodstream than endothelial cells in capillaries elsewhere in the body,
  • processes from astrocytes surround the epithelial cells of the bbb providing biochemical support to the epithelial cells
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9
Q

What are the structural differences between brain microvescular endothelial cells and normal endothelial cells?

A

Absence of fenestrations and more extensive tight junctions are found in brain microvascular endothelial cells

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10
Q

What are the functional differences between brain microvescular endothelial cells and normal endothelial cells?

A

The brain microvescular endothelial cell is

  • impermeable to most substances
  • sparse pinocytic vesicular transport
  • increased expression of transport and carrier proteins: receptor mediated endocytosis
  • no gap junctions, only tight junctions
  • limited paracellular and Transcellular transport
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11
Q

What is the function of the blood brain barrier?

A
  • Isolates brain from peripheral circulation
  • interface between blood that supplies nutrients to the brain and enables the brain to regulate homeostasis of its environment to function properly
  • selective permeability to the CNS
  • limits central uptake of large molecules
  • limits central uptake of hydrophilic compounds
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12
Q

What is the anatomy of the blood CSF barrier?

A

Tight junction of the choroid plexus cells

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13
Q

What is the function of the blood CSF barrier?

A
  • selective pass of substances from capillaries

- limiting drug penetration through choroid plexus

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14
Q

What is the anatomy of the CSF brain barrier?

A
  • ventricular lining cells

- membrane of brain surface

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15
Q

What is the function of the CSF brain barrier?

A

Surrounds the peri-vascular space

16
Q

What is the importance of neuropeptides?

A
  • peptide hormones and neurotransmitters play major roles in regulation of most processes
  • endogenous neuropeptides including growth factors have been shown to be essential for brain development and brain function
  • peptide neuro pharmaceuticals possess enormous potential for treatment of many CNS diseases
17
Q

What is the implication of dopamine and Parkinson’s disease?

A
  • PD= chronic progressive neurodegenerative disorder caused by selective degeneration of dopaminergic neurons in the brain leading to the significant depletion of dopamine
  • since PD is related to DA deficiency, first line treatment is to administer DA
  • DA does not cross the bbb naturally as it is to polar
  • we treat PD with L-dopa: transported across bbb by amino acid transporters system.
  • once across, L-dopa is decarboxylated to dopamine by amino acid decarboxylase (L DOPA acts as a pro drug)
18
Q

What are the limitations of the current L dopa treatment for PD?

A
  • sensitive to Physicochemical and enzymatic degradation
  • undergoes rapid FPM (peripheral decarboxylation)
  • only 1% of given dose is transported unchanged to the brain
  • multiple dosing is required as half life is 90min
  • large dose related side effects: severe nausea, vomiting orthostatic hypotension
  • co admin of AADC inhibitors leads to severe side effects like nausea, memory loss and nervousness
19
Q

What implications does nano encapsulation of L DOPA have?

A
  • improved therapeutic efficacy and reduced toxic side effects
  • stabilises drug and protects it
  • facilitates movement of drug across barriers
  • drug release is in a controlled manner
  • drug in neuropeptides is unaltered
  • capable of bypassing p-glycoprotein transporters
  • capable of longer circulation