Neuro and Pulmonary Toxicity

Question 1

How does MPP+ get into brain?

Answer 1

MPTP lipophilic crosses BBB

OCT3, organic cation transporter on astrocytes takes up converts to MPP+ (MAO).

DAT transporters take up into neurones. Loss of dopaminergic neruones.

Question 2

Toxicity of MPP+?

Answer 2

Accumulates in mitochondria, inhibiting mitochondrial complex 1 of ETC.
-Reducing ATP production
-Production of ROS (oxidative stress)
-Mitochondrial permeability pore to open =swelling

Question 3

MPP+ and dopamine?

Answer 3

MPP+ high affinity for VMAT2 dopamine distributed to cytoplasm, leak out from DAT. Dopamine oxidised = oxidative stress. Lipid peroxidation. Membrane integrity lost. Cell death (neurons of nigrostriatal pathway)

Question 4

Paraquat absorption

Answer 4

Oral exposure most common route.
Main target lungs.
Only 1-5% of dose absorped in small intestine.

Question 5

Toxicity of Paraquat

Answer 5

20-40 mg/kg toxic. 240mg/kg lethal.
Kills lungs pulmonary haemorrhage, fibrosis, alveolar inflammation, oedema.

Question 6

Mechanism of Paraquat Toxicity

Answer 6

Substrate of polyamine uptake system (PUS). PUS expressed on type 1 and 2 alveolar cells and bronchiolar Clara cells.

Fibroblasts produce collagen - fibrosis - death

Question 7

Paraquat toxicity on Type 1 alveolar cells

Answer 7

In type 1 cause produce ROS, swells alveolar space, lose lung function.

ROS=DNA damage, lipid peroxidation, protein damage.

Question 8

Paraquat toxicity on Type 2 alveolar cells

Answer 8

Alveolitis, drawing of fluid from the capillaries, oedema, massive inflammation.