Dissertation/Thesis Abstract

Impact of Sigma-1 and Sigma-2 Receptor Ligand on Microglial Inflammatory Response
by Bhandari B. C., Suyesha, M.S., Southern Illinois University at Edwardsville, 2019, 67; 22592438
Abstract (Summary)

Neuroinflammation is protective response of brain towards any stimuli such as pathogens, injury, and cellular debris. The response involves activation of glial cells (microglia and astrocytes), production of pro-inflammatory cytokines, reactive oxygen and nitrogen species. Microglia is the primary player of neuroinflammation. In various neurodegenerative diseases such as Alzheimer’s disease (AD), microglia are persistently activated by variety of stimuli such as amyloid-beta plaques and soluble oligomers, cytokines, purines released form dying neurons and tau proteins leading to chronic neuroinflammation. Sigma-receptors are a relatively new group of intracellular receptors that are expressed in microglia and shown to modulate various factors involved in inflammatory response. This research work is done to evaluate the effect of a pan-selective sigma-receptor ligand, Cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexhydrobenz[e]indolehydrochloride (BBZI), in modulating the BV2 microglial inflammatory response to lipopolysaccharide (LPS) using cell viability and nitric assay in addition to mRNA expression by RT-qPCR.

When looking at cell viability, a significant reduction was observed at different molar concentration of BBZI (p = 0.0253) and LPS (0.0002). Cell viability significantly decreased at 1000nM BBZI compared to vehicle (p = 0.0312, Tukey). A significant increase in cell viability was observed when comparing 10 ng/ml of LPS in vehicle (p = 0.0005, Tukey). However, there was no significant interaction between LPS and BBZI (p = 0.9820, Two-way ANOVA).

Only LPS showed significant impact in nitric oxide production (BBZI: p = 0.8579, LPS: p < .0001, BBZI*LPS: 0.3191, Two-way ANOVA). Nitric oxide significantly increased as the concentration of LPS dose-dependently increased, with all concentrations being significantly different from one another (p < 0.0001 for each, Tukey).

A significant impact in mRNA expression of sigmar1 (p = 0.0025), tmem97/sigmar2 (p < 0.0001), inos (p < 0.0001), il-1β (p < 0.0001) and tnfα (p < 0.0001) was observed with LPS treatment only. LPS significantly decreased mRNA expression for sigmar1 and tmem97/sigmar2 at 100 ng/ml in comparison to 10 ng/ml (p = 0.025 and p=0.006 respectively) and vehicle (p = 0.002 and p<0.0001 respectively, Tukey). In contrast, LPS significantly increased mRNA expression of inos, il-1β and tnfα at 100 ng/ml in comparison to 10 ng/ml (p = 0.0005, p=0.002 and p<0.0001 respectively, Tukey) and vehicle (p < 0.0001for each, Tukey). BBZI did not have any significant effect on the expression of inos (p = 0.8111), tnfα (p = y0.667) and il-1β (p = 0.7003). There was no significant interaction between LPS and BBZI for inos (p = 0.1355), tnfα (p = 0.167) and il-1β (p = 0.5929). This study concludes while sigma receptors could be associated with microglial inflammation, pan-selective compound, BBZI does not mitigate neuroinflammation in BV2 cells at 24 hours treatment time. Further pharmacological research work evaluating its potential mechanism of action, the effects of pre-treatment and time-course needs to be done to fully ascertain the effects of BBZI in BV2 cells.

Indexing (document details)
Advisor: Witt, Ken A.
Commitee: Sandoval, Karin E., Schober, Joseph S.
School: Southern Illinois University at Edwardsville
Department: Pharmaceutical Sciences
School Location: United States -- Illinois
Source: MAI 81/3(E), Masters Abstracts International
Subjects: Pharmacology, Neurosciences
Publication Number: 22592438
ISBN: 9781088376294
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