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Investigation into the anti-inflammatory properties of metformin as a potential therapeutic agent for lower back pain

Ramanathan, Rahul (2019) Investigation into the anti-inflammatory properties of metformin as a potential therapeutic agent for lower back pain. Undergraduate Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Intervertebral disc degeneration (IDD) is closely related to heightened inflammation in the annulus fibrosis (AF) and nucleus pulposus (NP) cells in the intervertebral disc. Gene expression and enzymatic activity of catabolic factors that degrade the extracellular matrix, such as matrix metalloproteinase 13 (MMP-13), IL-1β, PGE2 and COX-2, can be triggered by inflammatory as well as mechanical (tensile/compressive) stresses. An imbalanced matrix homeostasis, i.e., enhanced catabolic and suppressed anabolic activity, has been shown to contribute to disc degeneration and associated discogenic low back pain. There have been multiple efforts to curtail this imbalance through both therapeutic and preventative measures.

Developed in 1922, metformin has recently been the most widely used oral medication for type II diabetes in the United States. Traditionally, metformin has been used to decrease hepatic gluconeogenesis and increase insulin sensitivity by inhibiting mitochondrial pathways in diabetic patients. It has also been noted to exhibit anti-inflammatory properties through upregulation of the AMPK pathway, leading to various pro-autophagy and anti-inflammatory-related responses in hepatocytes. However, it is still unclear how metformin influences disc cellular response to inflammatory stress and the mechanism in which it enacts its effects. Hence, the objective of this study is to elucidate the effects of metformin on expression of key pro-inflammatory, catabolic, and anabolic factors within rat AF cells in response to inflammatory stimulation and mechanical tensile stress.

Five Fischer 344 rats were sacrificed and their spines isolated. AF cells were cultured and plated in flexible silicone membrane-based six-well plates. Wells were split into eight groups and subjected to metformin, IL-1β, mechanical stretch, and combined treatments. Relative gene expressions of MMP-13, COX-2, iNOS, AGC, and Col1 were assessed with qRT-PCR, and downstream PGE2 production was quantified with ELISA.

Metformin in the presence of the combined stress treatments (M+IL/S) significantly decreased COX-2 and iNOS expression, decreased PGE2 production, and increased Col1 expression. The lack of metformin-mediated suppression of inflammatory response in the non- stretch groups indicates that metformin may be enacting its effects through a stretch-dependent manner.

These results suggest a foundation for pursuing further research into metformin’s potential role as an anti-inflammatory agent for curtailing intervertebral disc degeneration.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ramanathan, Rahulrar122@pitt.edurar122
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSowa, Gwendolyngas26@pitt.edugas26
Committee CoChairPurmessur, Devinawalter.368@osu.edu
Committee MemberMahboobin, Arasharm19@pitt.eduARM19
Committee MemberVo, Nnvv1@pitt.eduNVV1
Date: 1 May 2019
Date Type: Publication
Defense Date: 15 April 2019
Approval Date: 1 May 2019
Submission Date: 30 April 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 45
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
University Honors College
Degree: BS - Bachelor of Science in Engineering
Thesis Type: Undergraduate Thesis
Refereed: Yes
Uncontrolled Keywords: N/A
Date Deposited: 01 May 2019 12:43
Last Modified: 01 May 2019 12:43
URI: http://d-scholarship.pitt.edu/id/eprint/36663

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