Effects of β-funaltrexamine on lipopolysaccharide-induced inflammation and behavior

Inflammation plays a crucial role in the development, progression, and severity of many prevalent systemic and neurological pathologies. A growing body of evidence has found that inflammation is a key aspect of cardiovascular disease, autoimmune disorders, cancer, neurodegenerative diseases, and neuropsychiatric conditions. Consequently, there is a critical need to develop targeted pharmaceuticals to mitigate systemic inflammation and inflammation-induced behavioral deficits. Our lab has previously demonstrated that acute β-FNA has selective anti-inflammatory effects in normal human astrocytes and reduces systemic inflammatory mediators and anxiety- and sickness-like behavior in male mice, predominantly through inhibition of p38 MAPK and NF-κB. The purpose of this study was to extend our knowledge of the cell-specific effects of acute β-FNA treatment using microglial cells, as well as study chronic pre-treatment effects on systemic inflammation and inflammation-induced behavioral deficits using a preclinical model. BV2 murine microglial cells were co-incubated with β-FNA and LPS at various times, while osmotic drug pumps were surgically inserted into mice that continually dispensed β-FNA for six days prior to LPS injection. Depressive-, anxiety-, and sickness-like behaviors were measured 24h after LPS injection, and then mice were terminated, and plasma, frontal cortex, hippocampus, and spleen tissues were harvested. CCL2, CXCL10, and IL-1β levels were measured in cell supernatant, CCL2 and CXCL10 were measured in frontal cortex, hippocampus, and spleen tissues, and IL-1β and corticosterone were measured in mouse plasma via ELISA. IDO1 and NLRP3 transcription were quantified via RT-qPCR from whole cell lysates and the afore-mentioned tissue homogenates. Additionally, p38 MAPK and STAT1 were quantified via Western blots in whole cell lysates. Acute β-FNA selectively reduced CCL2 and paradoxically potentiated LPS-driven IL-1β in BV2 cells, while exhibiting no effect on p38 MAPK, STAT1, NLRP3, or IDO1. Behavioral deficits were predominantly correlated with neuroinflammatory levels of CCL2, CXCL10, NLRP3, and IDO1. Additionally, chronic β-FNA pre-treatment greatly reduced systemic levels of CCL2 and CXCL10 and inhibited or abolished anxiety- and sickness-like behaviors. Interestingly, β-FNA increased frontal cortex inflammation and anxiety-like behavior under control conditions. Consequently, these studies provide additional insight into the actions and therapeutic potential of β-FNA and underscore areas that need further investigation.

Discipline thesis:degree_discipline

Biomedical Sciences

Grantor

Oklahoma State University

Year dc:date.issued

2024

Author dc:creator

• Hodge, Karissa

Advisor dc:contributor.advisor

• Davis, Randall

Committee members dc:contributor.committeemember

• Das, Subhas
• Volberding, Jennifer
• Arias, Hugo

Statement dc:rights

• Copyright is held by the author who has granted the Oklahoma State University Library the non-exclusive right to share this material in its institutional repository. Contact Digital Library Services at lib-dls@okstate.edu or 405-744-9161 for the permission policy on the use, reproduction or distribution of this material.

Language dc:language

en_US

Handle dc:identifier.uri

https://hdl.handle.net/20.500.14446/344858

OAI identifier oai:identifier

oai:openresearch.okstate.edu:20.500.14446/344858