The toxicology of antipsychotic drugs on human neuronal cells

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Hakeem, Israa Jameel (2019). The toxicology of antipsychotic drugs on human neuronal cells. University of Birmingham. Ph.D.

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Abstract

Antipsychotic medications are primarily used to manage several psychiatric disorders, such as schizophrenia and bipolar mania. They are also prescribed to manage neurodegenerative diseases symptoms including delusion, aggressiveness and agitation. Researches have suggested limiting the use of the first generation antipsychotics (FGAs) in elderly patients because of their adverse side-effects. The main aim of this study was to examine the effects of the first and second generation of antipsychotic drugs (SGAs) on neuronal (SH-SY5Y) and non-neuronal cells (COS7).

According to the LC50 values for the drugs investigated, chlorpromazine, trifluoperazine, olanzapine and quetiapine, they were specifically neurotoxic, since they were more potent in SH-SY5Y cells than in non-neuronal COS7 cells. In addition, of the FGAs tested in SH-SY5Y cells, they proved to be far more potent (LC50 5-6 μM) compared to the SGA drugs tested (LC50 85-100 μM). The major mechanism of cell death was apoptosis with regulated necrosis playing a minor role only with FGAs. Autophagy was not, however, involved. FGA induced apoptosis through the extrinsic pathway by activating caspase-8, and SGA induced cell death through the intrinsic pathway by activating caspase-9.

The involvement of Ca2+ pumps; SERCA2b and SPCA1a and the Ca2+ binding protein regucalcin (RGN) were investigated. From the results overexpression of SERCA2b and RGN showed a positive effect in the protection against the antipsychotic drug cell death, but no protection was observed with SPCA1a.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):