Alterations in Brain Metabolism in Pilocarpine-Induced Epilepsy and Potential Treatment Modalities.
Zahrani, Hamsa.
2018
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Abstract: Epilepsy is one of the most common chronic neurological disorders
and is manifested by abnormal hypersynchronized neuronal discharge. A cascade of molecular,
neuronal and metabolic alterations are involved in the process of developing epilepsy
(epileptogenesis). The exact mechanisms underlying epileptogenesis are still unclear. In
order to expand our knowledge and improve our underst... read moreanding of epilepsy, we have
investigated two main objectives. The first objective is identifying the role of HBP1 in
epilepsy. HBP1 acts as Wnt repressor, and epileptogenesis occurs when Wnt signaling is
up-regulated in an HBP1 knockout mouse. Importantly, deletion of 9 genes in the HBP1
chromosomal region in human populations (7q22.3) is associated with seizure or abnormal
EEG, indicating the mouse model may recapitulate human disease. Utilizing 1H and 13C NMR
spectroscopy, the metabolic profile of HBP1 knock out and wild type has been quantified in
hippocampus, but no significant differences were detected. The second objective in this
project was testing the efficacy of the EGCG/DAC combination (a HBP1 inducer) and observing
its effect on the metabolism of normal and epileptogenic brain. The EGCG/DAC is proposed to
be protective against the development of epilepsy. Using NMR the metabolite concentrations
were obtained. A comparison between pilocarpine induced status epilepticus and control mice
revealed a series of significant metabolite alterations. In hippocampus, GABA, AMP, NAD+,
were significantly decreased in the pilocarpine group compared to control mice. In
contrast, concentrations of IMP, lactate, UMP and myo-inositol were significantly increased
in hippocampus. Glutamate and NAA were significantly decreased in pilocarpine group. On the
other hand, glutamine was significantly up regulated in pilocarpine mice in both brain
regions. Also, comparisons between pilocarpine and control in the background of being
treated with the drugs versus pilocarpine and control groups respectively, showed
significant increase of fumarate and UDP-glucuronate in treated control and no significant
change was detected in the treated pilocarpine mice. Additionally, a comparison between
treated pilocarpine and treated control groups displayed no significant difference, except
for the significant increase of the O-phosphoethanolamine in treated control in contrast to
ethanolamine which increased significantly in treated pilocarpine group. In conclusion,
besides investigating the essential signaling pathway Wnt/𝛽-catenin and HBP1, we have
examined the effect of EGCG/DAC in epilepsy in order to develop a paradigm shift in
treating and preventing epilepsy disorders.
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: James Baleja.
Keyword: Pharmacology.read less - ID:
- xs55mq51n
- Component ID:
- tufts:25449
- To Cite:
- DCA Citation Guide EndNote
