Elsevier

Experimental Neurology

Volume 267, May 2015, Pages 107-114
Experimental Neurology

Regular Article
Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats

https://doi.org/10.1016/j.expneurol.2015.03.006Get rights and content

Highlights

  • Moderate exercise increases the expression of inhibitory neurotransmitter, enkephalin in DRG of Type 1 diabetic (T1D) rats.

  • Moderate exercise reduces the inflammatory and stress related markers in the DRG of Type 1 diabetic rats.

  • Moderate exercise impedes the development of neuropathy with a decrease in voltage gated ion channels in the DRG of T1D rats.

Abstract

Painful neuropathy is a long-term and difficult to treat complication of diabetes that affects 25% of diabetic patients and interferes with their quality of life. Unfortunately, available medical treatments are relatively ineffective due to dependency and addiction. Emerging research indicates that moderate-to-vigorous physical activity provides health-related benefits. However, adequate data is not available to determine whether regular exercise would prevent or delay the development of painful neuropathy in subjects with Type 1 diabetes. This study demonstrates the significance of moderate exercise in the amelioration of pain in animals with Type 1 diabetes after 6 weeks of exercise paradigm. After initial acclimatization, streptozotocin-diabetic animals were placed in motorized running wheels for 60 min per day, for five days a week for 6 weeks starting at one week after diabetes. A growing body of evidence suggests that the release of proinflammatory cytokines plays an important role in the development and persistence of pain. This study demonstrates that moderate exercise increases the expression of inhibitory neurotransmitter enkephalin and also reduces the presence of a number of proinflammatory cytokines in the dorsal root ganglia (DRG), subsequently impeding the development of neuropathy along with a decrease in the voltage gated ion channels in the DRG. Overall, the study suggests that exercise may provide an alternate route of treatment of painful neuropathy in Type 1 diabetic subjects by decreasing the use of pain medications, thereby providing a more useful and efficient way for pain management.

Introduction

Pain is a significant consequence of diabetic neuropathy. Diabetes mellitus is the most common cause of neuropathy in the United States, and 25% of diabetic patients with neuropathy suffer from neuropathic pain, resulting in a significant adverse effect on quality of life measures (Van Acker et al., 2009). Unfortunately, available medical treatment is relatively ineffective with limited efficacy and is complicated by side effects and dependency (Barbano et al., 2003). Accumulating evidence suggests that the activation of inflammatory cascades in the peripheral and central nervous systems plays a key role in the development and persistence of neuropathic pain states induced by physical or toxic injury to peripheral nerve (Gonzalez-Clemente et al., 2005, Herder et al., 2009, King, 2008).

In diabetes, there is evidence of systemic immune activation. Patients with painful neuropathy show increased levels of IL-2 in blood and increased levels of TNFα mRNA and protein in blood (Uceyler et al., 2007). The elevated level of serum TNFα in Type 1 diabetes patients suggests that TNFα may play a pathogenic role in the development of diabetic neuropathy (Gonzalez-Clemente et al., 2005, Kaul et al., 2010). Studies on patients with Type 2 with or without polyneuropathy exhibit a different immune profile and specific neuropathic deficits, suggesting that inflammation is associated with diabetic neuropathic impairments involving a number of immune mediators such as C-peptide, IL-2 receptor, IL1β and TNFα (Empl et al., 2001, Uceyler et al., 2007). Previously, we have shown that the inflammatory mediators in the dorsal root ganglia are altered with the development of pain in Type 2 model of diabetes (Galloway and Chattopadhyay, 2013). Although earlier studies have demonstrated the effects of moderate to intense physical exercise on pain perception (Rossi et al., 2011), not many have shown the effects of moderate exercise that may change the endogenous opioid content as well as the levels of inflammation in DRG of Type 1 diabetic animals with painful neuropathy. Hyperglycemia causes p38 mitogen-activated protein (p38) kinase activation (Igarashi et al., 1999), which can be induced by changes in the release of proinflammatory cytokines. Previously we have shown that viral vector mediated release of enkephalin modified the activation of p38 MAPK in Type 1 diabetic DRG (Chattopadhyay et al., 2008). This study also explores the possibility whether exercise can alter the endogenous opioid, enkephalin and stress associated markers, thus reducing pain related behaviors. It is well known that the heat shock protein (HSP) molecular chaperones protect cells from stressful insults. Diabetes is generally associated with lower HSPs (Padmalayam, 2014). A low HSP state promotes increased activation of inflammatory cytokines (Hooper and Hooper, 2009). Moreover, exercise training is a non-pharmacological and noninvasive treatment method. To avoid any intense exercise (up to 33 m/min for 20 min) induced increases in inflammatory markers and adverse effect on hyperglycemia in Type 1 diabetic animals (Bortolon et al., 2012), this study chose a moderate exercise regimen (10 m/min for 60 min). The current study explored the effect of moderate exercise on pain perception and also on the changes in enkephalin as well as the inflammatory mediators in the peripheral nervous system of Type 1 diabetic animals after 6 weeks of exercise regimen. Hence, moderate exercise may provide an alternative therapeutic approach for this disabling and difficult-to-treat complication of diabetes avoiding systemic side effects of the treatment.

Section snippets

Experimental design

Experiments were performed on male Sprague Dawley rats weighing approximately 250–280 g (Charles River, USA) in compliance with approved institutional animal care and use protocols. The rats were divided into four groups: naïve controls (n = 8), control exercise (n = 8), diabetic sedentary (n = 8) and diabetic exercise (n = 8) and were trained to run in the motorized wheels for six weeks. For the nociceptive analysis, animals from each group were tested after six weeks of exercise training by a blinded

Exercise did not alter body weight and blood glucose levels in STZ-diabetic animals

The Type 1 model of STZ-diabetic rats presented lower body weight compared to control rats. The change in body weight in the STZ-diabetic sedentary group was not significantly different than that of the STZ-diabetic exercise group (Fig. 1a). Physical exercise did not decrease the blood glucose levels in diabetic exercised animals after 6 weeks of exercise regimen. Furthermore, the blood glucose level was also unaffected by exercise in control exercised rats (Fig. 1b). We measured blood glucose

Discussion

Our data clearly demonstrates that exercise delays the progression of thermal and mechanical hyperalgesia as well as cold allodynia in STZ-induced diabetes. This study focuses on the benefit of moderate exercise to reduce the risk of exercise induced hypoglycemia and inflammation in Type 1 diabetic animals. Studies have shown that there is a modest increase in IL-6, IL1β and TNF-α in Type 1 diabetic patients following intense exercise (Campbell et al., 2014, Nemet et al., 2002). The present

Authors' contributions

HY carried out the behavior tests and biochemical assays. DI and MF carried out the behavior tests and exercise regimen. VT carried out biochemical assays and reviewed the manuscript. MC contributed to the design and analysis of the study, behavior test and wrote the manuscript.

Conflict of interests

The authors declare that they have no conflict of interests.

Acknowledgments

This work was funded by American Diabetes Association (Grant #7-12-BS-021) to MC. We acknowledge Jessica Meyers, Ryan Pattnaik and Valerie Zeer for helping with the animal exercise.

References (42)

  • J.R. Bortolon

    Persistence of inflammatory response to intense exercise in diabetic rats

    Exp. Diabetes Res.

    (2012)
  • M. Brownlee

    The pathobiology of diabetic complications: a unifying mechanism

    Diabetes

    (2005)
  • C.R. Bruce et al.

    Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism

    Diabetes

    (2003)
  • M.D. Campbell

    Metabolic implications when employing heavy pre- and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes patients: a randomised clinical trial

    PLoS One

    (2014)
  • L.J. Chassin et al.

    Intense exercise in type 1 diabetes: exploring the role of continuous glucose monitoring

    J. Diabetes Sci. Technol.

    (2007)
  • M. Chattopadhyay et al.

    Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy

    J. Neurosci.

    (2008)
  • Y.W. Chen et al.

    Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats

    Anesth. Analg.

    (2013)
  • H.T. Cheng

    p38 mediates mechanical allodynia in a mouse model of type 2 diabetes

    Mol. Pain

    (2010)
  • F.Q. Cunha et al.

    The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia

    Br. J. Pharmacol.

    (1992)
  • M. Empl

    TNF-alpha expression in painful and nonpainful neuropathies

    Neurology

    (2001)
  • J.M. Gonzalez-Clemente

    Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus

    Clin. Endocrinol.

    (2005)
  • Cited by (0)

    View full text