Thesis

Neuroprotective effects of cyclosporine A and GluR2 AMPA receptors against excitotoxicity in FVB/N and C57BL/6 mice

Glutamate (Glu) is an important excitatory neurotransmitter in the brain. It binds to ionotropic Glu receptors located in the postsynaptic membrane and allows calcium into the cell. Abnormally high levels of Glu can induce excitotoxicity (seizure), which results in high intracellular calcium, mitochondrial dysfunction, and cell death. It has been shown in vivo that FVB/N (FVB) mice are susceptible to Glu-induced excitotoxicity, while C57BL/6 (B6) mice are resistant. Previous studies have suggested that this might be due to calcium impermeable GluR2 α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (GluR2 AMPA) receptors. In order to determine whether GluR2 AMPA receptors play a role in susceptibility differences of FVB and B6 mice, two excitotoxic treatments were used. Glu was used to stimulate GluR2 AMPA receptors, while potassium chloride (KCl) was used to bypass Glu receptors and depolarize the cell via voltage-gated calcium channels. Additionally, Cyclosporine A (CsA) has also been shown to block mitochondrial permeability transition pores (mPTPs), which reduces calcium influx into the mitochondria and prevents dysfunction. Various concentrations of CsA were used to determine its effect on both mice during Glu excitotoxicity. Results showed that FVB mice expired and B6 mice survived Glu excitotoxicity alone, while both strains expired after KCl excitotoxicity alone. CsA was neuroprotective at all doses in susceptible FVB mice during Glu excitotoxicity, but was detrimental towards resistant B6 mice at high concentrations. CsA was also neuroprotective against KCl-induced excitotoxicity in both strains of mice. This suggests that GluR2 AMPA receptors are responsible for susceptibility differences of the two mice, but something downstream of the GluR2 AMPA receptors is responsible for regulating cell death during excitotoxicity. Furthermore, these findings suggest that while CsA appears to have advantageous properties, certain subjects might be sensitive to high doses of the drug.

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