Low-to-Moderate Intensity Exercise Reverses Nerve Growth Factor Upregulation in Osteoarthritic Rats

Background & Aims

In an era marked by an aging population and rising obesity rates, osteoarthritis (OA) has emerged as a leading cause of chronic pain and disability globally. Beyond the pain it inflicts, OA contributes to a spectrum of problems including depression, cognitive impairment, and poor quality of life [1,2]. Established treatment guidelines endorse exercise as a core therapy for OA management with/without pharmacological interventions [3,4]. In addition to pain relief, exercise may also improve mental health and cognitive function [5]. However, how exercise relieves pain is not yet fully understood. Therefore, we aimed to explore the effects of a two-week exercise intervention on pain-related behavior, general well-being, and cognitive function in an OA rat model. In particular, we wanted to elucidate the influence of exercise on molecular markers contributing to peripheral sensitization, cytokines (IL-1? and TNF-?) and nerve growth factor (NGF), a promising target for pain control in OA.

Methods

OA was induced by intra-articular injection of monoiodoacetate (MIA; 2 mg) in male Wistar rats. Saline-control rats received the same volume of saline injection [6]. On day 7 post-MIA, rats were randomly assigned to low-to-moderate (12 m/min) or moderate-to-high (18 m/min) exercise intensity groups. Treadmill exercise, lasting 30 min/day for 5 consecutive days, followed by a 2-day rest was conducted over a two-week period (10 days in total). Pain-related behavior was assessed using the von Frey and weight-bearing test; general well-being was evaluated in the burrowing test. These tests were performed prior to OA induction and at weekly intervals until day 28. The cognitive performance of the rats was assessed on day 27 using the novel object recognition test (NORT). On day 28, animals were sacrificed and knee tissue was collected for qRT-PCR analysis of cytokines (IL-1? and TNF-?) and NGF. The results were analyzed by one-way/two-way repeated-measures ANOVA (Tukey post-hoc analysis).

Results

Both exercise intensities reversed MIA-induced mechanical hypersensitivity and weight-bearing deficits (P ? 0.027 vs MIA-control). The beneficial effects on pain-related behavior were also present on day 28, a week post-exercise cessation (P ? 0.004). However, higher exercise intensity depressed burrowing behavior on day 20 (P = 0.005 vs saline-control), while lower intensity exercise had no significant impact on burrowing (P ? 0.77 vs saline-control). Notably, lower intensity exercise improved the cognitive performance of rats with OA in NORT (P = 0.01 vs MIA-control), while higher intensity exercise failed to produce similar benefits (P > 0.99 vs MIA-control). Finally, lower intensity exercise reversed the increase in Ngf mRNA expression (P = 0.02 vs MIA-control), whereas higher exercise intensity did not attenuate Ngf mRNA upregulation (P = 0.82 vs MIA-control). Il-1? and Tnf-? mRNA levels remained upregulated with both exercise intensities (P ? 0.22 vs MIA-control).

Conclusions

While both exercise intensities effectively mitigated pain-related behavior (with the effects persisting after exercise cessation), low-to-moderate intensity exercise may offer more benefits. It reversed cognitive deficits without detrimental effects on animal well-being. Importantly, lower intensity exercise prevented the upregulation of Ngf in knee tissue, a crucial mediator of OA pain.

References

1.Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. 2.
2.Al-Khazraji BK, Appleton CT, Beier F, Birmingham TB, Shoemaker JK. Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: a narrative review. Osteoarthritis Cartilage. 2018 Apr;26(4):462-470.
3.Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, Callahan L, Copenhaver C, Dodge C, Felson D, Gellar K, Harvey WF, Hawker G, Herzig E, Kwoh CK, Nelson AE, Samuels J, Scanzello C, White D, Wise B, Altman RD, DiRenzo D, Fontanarosa J, Giradi G, Ishimori M, Misra D, Shah AA, Shmagel AK, Thoma LM, Turgunbaev M, Turner AS, Reston J. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020 Feb;72(2):220-233.
4.Rausch Osthoff AK, Niedermann K, Braun J, Adams J, Brodin N, Dagfinrud H, Duruoz T, Esbensen BA, Günther KP, Hurkmans E, Juhl CB, Kennedy N, Kiltz U, Knittle K, Nurmohamed M, Pais S, Severijns G, Swinnen TW, Pitsillidou IA, Warburton L, Yankov Z, Vliet Vlieland TPM. 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018 Sep;77(9):1251-1260.
5.Mandolesi L, Polverino A, Montuori S, Foti F, Ferraioli G, Sorrentino P, Sorrentino G. Effects of Physical Exercise on Cognitive Functioning and Wellbeing: Biological and Psychological Benefits. Front Psychol. 2018 Apr 27;9:509.
6.Nasti? K, Pecikoza U, Labudovi?-Borovi? M, Kotur-Stevuljevi? J, Micov A, Jovanovi? A, Tomi? M, Stepanovi?-Petrovi? R. The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis. Biomed Pharmacother. 2023 Oct;166:115360.

Presenting Author

Katarina Nastic

Topics

Mechanisms: Biological-Molecular and Cell Biology

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Low-to-Moderate Intensity Exercise Reverses Nerve Growth Factor Upregulation in Osteoarthritic Rats

Background & Aims

Methods

Results

Conclusions

References

Presenting Author

Katarina Nastic

Poster Authors

Katarina Nastic

Uroš Pecikoza

Miroslav Dinic

Emilija Brdari

Ana Micov

Aleksandar Jovanovic

Maja Tomic

Radica Stepanovic-Petrovic

Topics

IASP 2024 World Congress on Pain