Alterations in Brain Metabolism in Pilocarpine-Induced Epilepsy and Potential Treatment Modalities.
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 ... read moreunderstanding 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