Novel insights into the nervous system affected by prolonged hyperglycemia.

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. KEY MESSAGES: Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.

Chemotherapy-induced neuropathies-a growing problem for patients and health care providers.

INTRODUCTION: Chemotherapy-induced neuropathies are one of the most common side effects of cancer treatment, surpassing bone marrow suppression and kidney dysfunction. Chemotherapy effects on the nervous system vary between different classes of drugs and depend on specific chemical and physical properties of the drug used. The three most neurotoxic classes of anti-cancer drugs are: platinum-based drugs, taxanes, and thalidomide and its analogs; other, less neurotoxic but also commonly used drugs are: bortezomib, ixabepilone, and vinca alkaloids. METHODS: Here, in this paper, based on our experience and current knowledge, we provide a short review of the most common, neuropathy-inducing anti-cancer drugs, describe the most prevalent neuropathy symptoms produced by each of them, and outline preventive measures and treatment guidelines for cancer patients suffering from neuropathy and for their health care providers. RESULTS: Patients should be encouraged to report any signs of neuropathic pain, alteration in sensory perception, tingling, numbness, burning, increased hot/cold sensitivity and motor dysfunctions as early as possible. If known neurotoxic chemotherapeutics are used, a neurological examination with electrophysiological evaluation should be implemented early in the course of treatment so, both patients and physicians would be better prepared to cope with possible neurotoxic effects. CONCLUSIONS: The use of neurotoxic chemotherapeutics should be closely monitored and if clinically permitted, that is, if a patient shows signs of cancer regression, drug doses should be reduced or combined with other less neurotoxic anti-cancer medication. If not counteractive, the use of over the counter antineuropathic supplements such as calcium or magnesium might be encouraged. If physically possible, patients should also be encouraged to exercise regularly and avoid factors that might increase nerve damage such as excessive drinking, smoking, or sitting in a cramped position.

RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice.

Peripheral neuropathy and insensate limbs and digits cause significant morbidity in diabetic individuals. Previous studies showed that deletion of the receptor for advanced end-glycation products (RAGE) in mice was protective in long-term diabetic neuropathy. Here, we tested the hypothesis that RAGE suppresses effective axonal regeneration in superimposed acute peripheral nerve injury attributable to tissue-damaging inflammatory responses. We report that deletion of RAGE, particularly in diabetic mice, resulted in significantly higher myelinated fiber densities and conduction velocities consequent to acute sciatic nerve crush compared with wild-type control animals. Consistent with key roles for RAGE-dependent inflammation, reconstitution of diabetic wild-type mice with RAGE-null versus wild-type bone marrow resulted in significantly improved axonal regeneration and restoration of function. Diabetic RAGE-null mice displayed higher numbers of invading macrophages in the nerve segments postcrush compared with wild-type animals, and these macrophages in diabetic RAGE-null mice displayed greater M2 polarization. In vitro, treatment of wild-type bone marrow-derived macrophages with advanced glycation end products (AGEs), which accumulate in diabetic nerve tissue, increased M1 and decreased M2 gene expression in a RAGE-dependent manner. Blockade of RAGE may be beneficial in the acute complications of diabetic neuropathy, at least in part, via upregulation of regeneration signals.

Immunohistochemical characterization of superior cervical ganglion neurons supplying porcine parotid salivary gland.

The main goal of our study was to investigate the chemical coding of the superior cervical ganglion (SCG) sympathetic neurons supplying the porcine parotid gland. Additionally, the chemical nature of the vicinal nerve fibers surrounding the parotid SCG perikarya was investigated. Fast blue (FB) retrograde tracing of the parotid gland and immunofluorescent labelling of SCG neurons were studied in juvenile female pigs. Microscopic analysis revealed that only ipsilateral SCG neurons were retrogradely labelled. The labelled neurons formed a discrete cluster in the middle and caudal region of the ganglion. Immunofluorescent labelling revealed that virtually all of the FB-positive parotid gland neurons were immunoreactive to tyrosine hydroxylase (TH), confirming their sympathetic nature. In addition to TH, the majority of the FB-positive neurons were found to be immunoreactive to calbindin (CB) and to a lesser extent for neuropeptide Y (NPY), leu-enkephalin (LENK) and galanin (GAL). In the close proximity of the FB-traced perikarya, a large number of immunoreactive (IR) vasoactive intestinal peptide (VIP-IR), pituitary adenylate cyclase-activating polypeptide (PACAP-IR), nitric oxide synthase (NOS-IR) processes were identified. Moreover, calcitonin gene related peptide-immunoreactive (CGRP-IR), substance P-immunoreactive (SP-IR), vesicular acetylcholine transporter (VAChT-IR), calretinin (CRT-IR), GAL-IR, LENK-IR and CB-IR protrusions were observed. The results of the present study provide a detailed characteristic of the location and neurochemical coding of sympathetic SCG neurons innervating the parotid salivary gland of the pig and lay ground for more advanced, clinical studies on salivary gland innervations.