Mouse Model Of Neuropathy Research Articles

Bone Marrow-Derived Mesenchymal Stem Cells Improve the Functioning of Neurotrophic Factors in a Mouse Model of Diabetic Neuropathy

Diabetic neuropathy is one of the most frequent and troublesome complications of diabetes. Although there has been a continuous increase in the incidence of diabetic neuropathy, treatments have yet to be found that effectively treat diabetic neuropathy. Neurotrophic factors are proteins that promote the survival of specific neuronal populations. They also play key roles in the regeneration of peripheral nervous system. Recent evidence from diabetic animal models and human diabetic subjects suggest that reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic neuropathy. One way to reverse this effect is to take advantage of the finding that bone marrow derived mesenchymal stem cells (BM-MSCs) promote peripheral nerve repair and the functioning of neurotrophic factors. Therefore, we speculated that treatment with BM-MSCs could be a viable therapeutic strategy for diabetic neuropathy. The present study was designed to examine the possible beneficial effect of BM-MSCs on functions of neurotrophic factors in diabetic neuropathy. To assess this possibility, we used an in vivo streptozotocin-induced diabetic neuropathy mouse model. Quantitative real-time polymerase-chain reacion showed that BM-MSCs significantly increase expression levels of neurotrophic factors. Also, BM-MSCs ameliorated nerve conduction velocity in streptozotocin-treated mice. These results may help to elucidate the mechanism by which BM-MSCs function as a cell therapy agent in diabetic neuropathy.

Diosgenin from Dioscorea nipponica Ameliorates Diabetic Neuropathy by Inducing Nerve Growth Factor

Diabetic neuropathy is characterized by axonal degeneration, demyelination, and atrophy in association with failed axonal regeneration, remyelination, and synaptogenesis. Recent reports suggest that reduced levels of nerve growth factor (NGF) may play a significant role in the pathogenesis of diabetic polyneuropathy. In this study, we investigated the regulation of NGF by steroid diosgenin (DG) in a diabetic neuropathy rodent model. We found that DG, the primary spirostane-type steroid in several Dioscorea species, increased NGF levels in the sciatic nerve of diabetic rats. Additionally, DG increased neurite outgrowth in PC12 cells and enhanced nerve conduction velocities in the diabetic neuropathy mouse model. DG-treated diabetic mice showed reduced disarrangement of the myelin sheath and increased area of myelinated axons by electron microscope studies and exhibited improvement in the damaged axons. Our data further suggest that DG increased the nerve conduction velocity through induction of NGF. Thus, our findings indicate that DG, a major sapogenin obtained from Dioscorea nipponica, reverses functional and ultrastructural changes and induces neural regeneration in a diabetic neuropathy model.

Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies

This study evaluated the role of 12/15-lipoxygenase, which converts arachidonic acid to 12( S)- and 15( S)-hydroxyeicosatetraenoic acids, in nitrosative stress in the peripheral nervous system and peripheral prediabetic and diabetic neuropathies. The experiments were performed in C57BL6/J mice made diabetic with streptozotocin or fed a high-fat diet and in human Schwann cells cultured in 5.5 or 30 mM glucose. 12/15-Lipoxygenase overexpression and activation were present in sciatic nerve and spinal cord of diabetic and high-fat diet-fed mice, as well as in human Schwann cells cultured in high concentrations of D-, but not L-glucose. 12/15-Lipoxygenase inhibition by cinnamyl-3,4-dihydroxy-α-cyanocinnamate (8 mg kg − 1 day − 1 sc, for 4 weeks after 12 weeks without treatment) alleviated the accumulation of nitrated proteins in the sciatic nerve and spinal cord, and large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss. 12/15-Lipoxygenase gene deficiency alleviated nitrosative stress and nerve conduction deficit, but not small sensory fiber neuropathy, in high-fat diet-fed mice. In conclusion, 12/15-lipoxygenase is implicated in nitrosative stress and peripheral neuropathy in mouse models of type 1 and early type 2 diabetes. Its presence in human Schwann cells and upregulation by high glucose suggest a potential involvement in human disease.

Immune cell–derived opioids protect against neuropathic pain in mice

The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as beta-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies.

Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons

We examined the efficacy of herpes simplex virus vector-mediated gene transfer of erythropoietin in preventing neuropathy in mouse model of streptozotocin-diabetes. A replication-incompetent herpes simplex virus vector with erythropoietin under the control of the human cytomegalovirus promoter (vector DHEPO) was constructed. DHEPO expressed and released erythropoietin from primary dorsal root ganglion neurons in vitro, and following subcutaneous inoculation in the foot, expressed erythropoietin in dorsal root ganglion neurons in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of erythropoietin prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibres in the skin and reduction of neuropeptide calcitonin gene-related peptide in the dorsal horn of spinal cord of the diabetic mice. We further investigated whether vector-mediated local expression of erythropoietin in dorsal root ganglion neurons can protect in vivo as well as in vitro hyperglycemia-induced axonal degeneration. Our findings show that the AKT/GSK-3beta dependent pathway plays an important role in mediating the protection of erythropoietin against diabetic neuropathy. Herpes simplex virus-mediated transfer of erythropoietin to dorsal root ganglia may prove useful in treatment of diabetic neuropathy.

Purinergic receptor antagonist modulates hyperalgesia and allodynia in a mouse model of neuropathy: Involvement of NO system and cytokine network at central and peripheral nervous system level

Purinergic receptor antagonist modulates hyperalgesia and allodynia in a mouse model of neuropathy: Involvement of NO system and cytokine network at central and peripheral nervous system level