Flipped lectures: PD modification

Question 1

Which mechanisms may underlie increase SNpc calcium load in excitotoxicity?

Answer 1

• Dysregulation of calcium channels. CaV²⁺_1.3 becomes upregulated
• Elevated glutamatergic input from the STN contributes to NMDA mediated excitotoxicity
• Neurons in the SNpc have low calbindin levels, thus are prone to exaggerated calcium levels.

Question 2

Strategies to reduce excitotoxicity of the SNpc

Answer 2

• deep brain stimulation of the STN. This may reduce glutamatergic excitation. It reduces dyskinesias in some patients.
• inhibition of Cav_1.3
• mGlu5 antagonists (postsynaptic excitatory glutamate receptor)

- mGlu4 agonists (presynaptic inhibitory receptor)

Riluzole reduces glutamatergic activity by promoting glial reuptake. It was not effective.

Question 3

mGlu5 antagonists

Answer 3

MTEP
This compound has been shown to reduce loss of dopaminergic cells in the striatum and reduce parkinsonism in primate models if given 5 days before and 30 days after MPTP administration.

However, the cell count was measured using TH staining which is not specific to dopamine cells (TH is NA precursor).

The fact that it is only effective if given before MPTP may mean it interferes with specific mechanism of MPTP, or that it is only effective if given before damage occurs.

Question 4

What is the evidence for mitochondrial dysfunction occurring in PD?

Answer 4

Sporadic PD patients show reduced activity in complex 1 of the ETC, which leads to increased ROS production, reduced ATP production and cell death.

Markers of oxidative stress are found in post-mortem P.D. brains - increased lipid peroxidation, protein carbonylation and DNA damage. There are also reduced levels of glutathione. However, it should be noted that postmortem tissue often represents end stage disease combined with years of treatment

Question 5

Why is the SNpc vulnerable to oxidative stress?

Answer 5

• high levels of dopamine metabolism by MAO-B, which produces free radicals
• They accumulate iron with age, which contributes to free radical formation by the fenton reaction.

Question 6

How can ROS lead to apoptosis?

Answer 6

1. Leads to swelling of mitochondria (mt), opening of mt Permeability Transition Pore (PTP) leading to collapse of mt membrane potential
2. Release of Cytochrome C, Apoptosis initiating factors etc.
3. Activation of Caspase Cascade
4. APOPTOSIS

Question 7

GDNF as a neuroprotective strategy

Answer 7

There is evidence for reduced GDNF in PD, which may increase neuronal vulnerability. Viral vectors delivering GDNF to the basal ganglia of MPTP treated primates increases TH cell count and reduces motor symptoms. It was shown to be effective in early trials delivering directly to the putamen, but were aborted in later trials due to lack of efficacy. This could be due to the effect of alpha-synuclein in inhibiting GDNF signaling, which is not present in MPTP models.

Rasagiline (MAO-B inhibitor) may promote GF production.