The treatment of diabetic neuropathy

Importance of XCL1/XCR1 interaction in diabetic neuropathy
Zychowska M, Rojewska E, Piotrowska A, Kreiner G, Mika J

Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland

Diabetes mellitus is one of the civilization diseases with rapidly increasing frequency of occurrence around the world, especially among populations of highly developed countries. In Poland, for example, there are about 2.5 million registered diabetics. Diabetic neuropathy is one of late complications of this disease and it is the most common type of neuropathic pain resulting from nerve damage, and often persisting after healing. However, its mechanism is not fully understood. Classical pathomechanisms of diabetic neuropathy development – being the consequence of high blood glucose levels (hyperglycemia) – are microvascular disturbances in nerves (observed in 50% of patients with chronic diabetes mellitus), and increase in sorbitol accumulation due to excessive glucose metabolism leading to a destruction of nerve fibers sheath.

However, many research centers are focusing their attention on the participation of cytokines in the processes responsible for the development of neuropathy. Cytokines are proteins with a very broad scope of action. This group consists not only of interleukins or TNF superfamilies members, but also chemokines – small molecules with well-established chemoattractant properties (i.e. inducing cell migration in areas of their secretion). Nevertheless, current studies indicate that chemokines are crucial in the development of neuropathic pain, including diabetic neuropathy.

The most common model used in studies on diabetic neuropathy development is a mice streptozotocin (STZ) model. Streptozotocin is a substance which, when administrated intraperitoneally, destroys beta cells (responsible for insulin secretion) in the pancreas leading to hyperglycemia. Our research [1] performed on mice streptozotocin model of diabetic neuropathy showed the activation of microglia (resident macrophage of the central nervous system) and increase of XCL1 and XCR1 protein level parallel with the development of neuropathic pain symptoms. Minocycline, on the other hand, a substance whose multidirectional mechanism of action has analgesic properties, not only prevents microglial activation, but also inhibits the increase in XCL1 and XCR1 levels, as reflected in a subsequent onset of neuropathic pain symptoms. This correlation raised the question of the actual contribution of XCL1 in the development of neuropathic pain with the participation of microglial cells. The response obtained after intrathecal administration of exogenous XCL1 to control animals confirmed that the concentration of XCL1 higher than homeostatic causes activation of microglia, and consequently, the appearance of neuropathic pain symptoms. This dependence was completed with the neuronal location of XCR1, which turned out to be crucial for rapid pronociceptive (acute pain) response observed after XCL1 administration. This neuronal stimulation due to the increase in XCL1 levels seems to result in the release of numerous pronociceptive factors activating microglial cells and leading to the development of pain symptoms.

The treatment of neuropathic pain, also the one associated with diabetes, is extremely difficult due to the loss of efficacy after long-term use of opioid analgesics (such as morphine). This forces researchers and clinicians to continually seek a more effective treatment regimen. The use of neutralizing antibodies for selected cytokines seems to be a promising avenue. Studies conducted in the streptozotocin model of diabetic neuropathy demonstrated that XCL1 neutralizing antibody not only affects the alleviation of already developed pain symptoms, but also prevents microglial activation induced by exogenous XCL1. These are pivotal results, since they indicate the possibility of using substances which act as potential analgesics not only on microglial cells (i.e. minocycline) but also on endogenous cytokines (i.e. neutralizing antibodies).

Joanna Mika PhD
Department of Pain Pharmacology


Acknowledgments: Supported by the National Science Centre grant 2012/05/N/NZ4/02416 (Krakow, Lesser Poland region, Poland); the statutory funds (Krakow, Lesser Poland region, Poland); and KNOW scholarship sponsored by the Ministry of Science and Higher Education of Poland (Warsaw, Mazovia region, Poland); to Zychowska M. and Piotrowska A.


1: Zychowska M, Rojewska E, Piotrowska A, Kreiner G, Mika J. Microglial Inhibition Influences XCL1/XCR1 Expression and Causes Analgesic Effects in a Mouse Model of Diabetic Neuropathy. Anesthesiology. 2016 Sep;125(3):573-89.

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