Animal Model Of Neuropathy Research Articles

Nerve pathology in animal models of neuropathies

To understand the pathology of axonal degeneration and demyelination in peripheral neuropathy, histological investigations in different animal models that mimic some aspects of human peripheral neuropathy are needed. Thus, in the following section of this special issue, the main pathological features of experimental autoimmune neuritis, animal models of chemotherapy-induced peripheral neuropath and of human inherited peripheral neuropathies (IPNs) will be illustrated. When possible, micrographs from animal models and selected human biopsy will be shown side by side.

Theories behind the effect of starch‑ and sucrose‑reduced diets on gastrointestinal symptoms in irritable bowel syndrome (Review).

Increased amounts of starch and sugar have been added to the diet in the Western world during the last decades. Undigested carbohydrates lead to bacterial fermentation and gas production with diffusion of water, causing abdominal bloating, pain and diarrhea. Therefore, dietary advice is the first line of treatment of irritable bowel syndrome (IBS), a disease characterized by abdominal pain and altered bowel habits without any organic findings. Recently, a diet with a reduction of starch and sucrose led to a marked effect on gastrointestinal (GI) symptoms. The mechanism is unknown, but three possible mechanisms are presented in the present review. First, functional variants of the enzyme sucrase-isomaltase (SI) have been described in IBS. A subgroup of patients with IBS may thus suffer from partial SI deficiency with reduced digestion of starch and sucrose. Second, fructose absorption is less efficient than glucose absorption, which may lead to a physiological fructose malabsorption when ingesting high amounts of sucrose. A third mechanism is that high-sugar diets causing hyperglycemia, hyperinsulinemia and weight gain have led to painful neuropathy in animal models; whereas, improved metabolic control in humans has led to improvement of neuropathy. Starch- and sucrose-reduced diets lead to decreased levels of C-peptide, insulin, gastric inhibitory peptide, leptin and weight reduction. These metabolic changes may reduce the excitability of the hypersensitive nervous system often found in IBS and, thereby, lead to the reduced symptoms found after the diet. In conclusion, further studies are needed to investigate the pathophysiology behind development of symptoms after starch and sucrose intake, and the mechanisms behind symptom relief after reduced intake.

Effectiveness of crocin of saffron (Crocus sativus L.) against chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial

Ethnopharmacological relevanceChemotherapy-induced peripheral neuropathy (CIPN) is one of the complications vexes patients treated with anti-cancer agents. Saffron has been demonstrated to attenuate symptoms of peripheral neuropathy in animal models. Also, there is a published clinical trial that investigated the pain relieving effect of saffron following nationally accepted rules and concluded that saffron was successful in alleviating pain symptoms in patients suffering from fibromyalgia. Aim of the studyWe aimed to determine the efficacy of crocin as a constituent of saffron in CIPN as the first report. Materials and methodsOne hundred and seventy-seven enrolled eligible patients (between December 2018 and March 2020) for study entry were cases demonstrating mild to severe symptomatic CIPN for at least a month. These cases were randomly assigned to two main groups including 15 mg crocin tablet, bid (30 mg total daily target dose) and placebo tablet for 8 weeks. A crossover study was performed with a 2-week washout period. Patient outcomes were measured once a week for 8 consecutive weeks. ResultsGrade of sensory, motor and neuropathic pain decreased considerably and significantly in the crocin group compared with placebo (P < 0.05). Observed toxicities were mild and adverse effects had no significant differences between the two groups (P > 0.05). ConclusionsCrocin considerably seems to be effective for relieving symptoms of CIPN in cancer patients receiving chemotherapy agents. However, further studies are needed about crocin with its beneficial neuropharmacological effects and lower adverse effects than the chemical agents such as antidepressants, lamotrigine, and gabapentin.

Sciatic Nerve Ligation Downregulates Mitochondrial Clusterin in the Rat Prefrontal Cortex

The concentration of the multifunctional protein clusterin is reduced in the plasma of subjects with degenerative scoliosis (DS) and carpal tunnel syndrome (CTS) but elevated in the cerebrospinal fluid of neuropathic pain patients successfully treated with spinal cord stimulation. The present work tries to increase the knowledge of pain-associated changes of plasma and brain clusterin by using an animal model of neuropathy. We studied the effects of sciatic nerve ligation on mechanical allodynia (von Frey test), anxiety (elevated plus maze test), plasma clusterin (enzyme-linked immunosorbent assay) and clusterin expression in the nucleus accumbens (NAC) and prefrontal cortex (PFC) of adult male Wistar rats (western blot). The possible modulatory role of high fat (HF) dieting was also studied, bearing in mind that obesity has been also reported to influence nociception, clusterin levels and prefrontal cortex activation. Animals with nerve ligation showed mechanical allodynia, anxiety and a marked downregulation of clusterin in the mitochondrial fraction of the prefrontal cortex. Animals fed on HF also exhibited a slight increase of the sensitivity to mechanical stimuli and anxiety; however, the diet did not potentiate the effects of nerve ligation. The results did not confirm a parallelism between neuropathy, obesity and alterations of plasma levels of clusterin, but strongly suggest that the protein could be involved in the functional reorganization of the prefrontal cortex which has been recently reported in chronic pain conditions.

Effect of mitoquinone (Mito-Q) on neuropathic endpoints in an obese and type 2 diabetic rat model

This study sought to determine whether the addition of mitoquinone (Mito-Q) in the diet is an effective treatment for peripheral neuropathy in animal models of diet-induced obesity (pre-diabetes) and type 2 diabetes. Unlike other anti-oxidative stress compounds investigated as a treatment for peripheral neuropathy, Mito-Q specifically targets mitochondria. Although mito-Q has been shown to reduce oxidative stress generated by mitochondria there have been no studies performed of the effect of Mito-Q on peripheral neuropathy induced by diet-induced obesity or type 2 diabetes. Diet-induced obese (12 weeks after high fat diet) or type 2 diabetic rats (12 weeks of high fat diet and 4 weeks after the onset of hyperglycemia) were treated via the diet with Mito-Q (0.93 g/kg diet) for 12 weeks. Afterwards, glucose utilization, vascular reactivity of epineurial arterioles to acetylcholine and peripheral neuropathy related endpoints were examined. The addition of Mito-Q to the diets of obese and diabetic rats improved motor and/or sensory nerve conduction velocity, cornea and intraepidermal nerve fibre density, cornea sensitivity and thermal nociception. Surprisingly, treating obese and diabetic rats with Mito-Q did not improve glucose utilization or vascular reactivity by epineurial arterioles to acetylcholine. These studies imply that mitochondrial dysfunction contributes to peripheral neuropathy in animal models of pre-diabetes and late-stage type 2 diabetes. However, improvement in peripheral neuropathy following treatment with Mito-Q was not associated with improvement in glucose utilization or vascular reactivity of epineurial arterioles to acetylcholine.

Coordination of Locomotor Activity in Transgenic C57Bl/6 Mice with Hereditary Neuropathy

Locomotor activity of C57Bl/6 mice with hereditary motor and sensory neuropathy (HMSN; an animal model of Charcot–Marie–Tooth, CMT, disease) was investigated in males and females of two ages (15 and 20 weeks) using the balance beam test (inclined beam); such indices as time of traveling via the beam to the shelter and number of slippings of the hindlimbs from the beam were recorded. It was found that C57Bl/6 mice spent dramatically more time for traveling than control C57Bl mice with no neuropathy, and the number of erroneous movements (slippings of the hindlimbs) during traveling in mice with HMSN was many times greater than that in the controls. The deficiency of control of locomotion in C57Bl/6 animals was found to be sex- and age-dependent. Females of this strain moved significantly slower than males of the same age categories; both 20-week-old males and females with HMSN spent significantly more time for traveling the test distance than 15-week-old animals and demonstrated more motor failures. Thus, symptoms of HMSN are more pronounced in females (probably due to the specificity of the hormonal background in the latter), and the severity of pathology increases with age. The balance beam test appears acceptable for obtaining easily interpretable quantitative characteristics of the quality of locomotion control in experimental animal models of neuropathies.

Physical activity and dietary interventions in diabetic neuropathy: a systematic review.

Diabetic neuropathy is a common and disabling disorder, and there are currently no proven effective disease-modifying treatments. Physical activity and dietary interventions in patients with diabetes and diabetic neuropathy have multiple beneficial effects and are generally low risk, which makes lifestyle interventions an attractive treatment option. We reviewed the literature on the effects of physical activity and dietary interventions on length-dependent peripheral neuropathy and cardiac autonomic neuropathy in diabetes. The electronic database PubMed was systematically searched for original human and mouse model studies examining the effect of either dietary or physical activity interventions in subjects with diabetes, prediabetes, or metabolic syndrome. Twenty studies are included in this review. Fourteen studies were human studies and six were in mice. Studies were generally small with few controlled trials, and there are no widely agreed upon outcome measures. Recent research indicates that dietary interventions are effective in modifying diabetic neuropathy in animal models, and there are promising data that they may also ameliorate diabetic neuropathy in humans. It has been known for some time that lifestyle interventions can prevent the development of diabetic neuropathy in type 2 diabetes mellitus subjects. However, there is emerging evidence that lifestyle interventions are effective in individuals with established diabetic neuropathy. In addition to the observed clinical value of lifestyle interventions, there is emerging evidence of effects on biochemical pathways that improve muscle function and affect other organ systems, including the peripheral nerve. However, data from randomized controlled trials are needed.

Gene therapy with the angiogenic neuropeptide secretoneurin ameliorates experimental diabetic neuropathy.

The pathogenesis of diabetic neuropathy remains enigmatic. Damage to the vasa nervorum may be responsible for this disorder. Recently, we showed that secretoneurin (SN) induces angiogenesis in hindlimb and myocardial ischemia. Moreover, beneficial effects were observed in wound healing. We therefore hypothesized that SN therapy may ameliorate diabetic neuropathy. We used db/db mice as animal model for neuropathy. Gene therapy was accomplished by intramuscular injection of SN plasmid along the sciatic nerve. Sciatic nerve motor and sensory conduction velocities were then measured for 9 wk. Nerve conduction velocities showed normal values in heterozygous mice for the observational period, but were severely reduced in homozygous mice in which velocities were significantly improved by SN, but not by control plasmid gene therapy. The reaction time in the tail-flick test improved significantly in SN-treated animals. The induction of growth of vasa nervorum seems to be part of the underlying mechanism. In addition, SN positively affected Schwann cell function in vitro and induced activation of important signaling pathways. Our observations suggest that SN exerts beneficial effects on nerve function in vivo and on Schwann cells in vitro. It therefore may be a promising treatment option for diabetic neuropathy.-Theurl, M., Lener, D., Albrecht-Schgoer, K., Beer, A., Schgoer, W., Liu, Y., Stanzl, U., Fischer-Colbrie, R., Kirchmair, R. Gene therapy with the angiogenic neuropeptide secretoneurin ameliorates experimental diabetic neuropathy.

Hypericum perforatum extract attenuates behavioral, biochemical, and neurochemical abnormalities in Aluminum chloride-induced Alzheimer’s disease rats

Alzheimer's disease (AD) is a progressive and ultimately fatal neurodegenerative diseases. Aluminum, a neurotoxic metal, is considered as the pathological hallmark and contributing factor of AD. Hypericum perforatum extract (HPE) is a neuroprotective agent that can prevent neurodegenerative pathologies through antioxidants, anti-inflammatory and regulating neurotransmitter release in animal model of neuropathy. The present study aimed to identify the potential neuroprotective of HPE on AlCl3-induced AD rats. Rats were treated with AlCl3 for 90days to induce behavioral, biochemical, and neurochemical similar to AD. From 31thday, the rats were treated with HPE for 60days. Our results showed HPE improved cognitive function in AlCl3-induced AD rats, and attenuated AlCl3-induced increase in acetylcholinesterase activity and glutamic acid level as well as decreased in noradrenaline and dopamine level. In addition, HPE reversed AlCl3-induced hippocampal pathology including amyloid-beta (Aβ) accumulation (elevated Aβ42 level and amyloid plaques), oxidative stress (increased reactive oxygen species level and thiobarbituric acid reactive substances level, decreased glutathione level and superoxide dismutase activity) and neuroinflammatory (increased mRNA expressions of Interleukin-1β, Interleukin-6, Tumor necrosis factor-α and major histocompatibility complex class II) in hippocampus of rats. Thus, HPE is conferred neuroprotection against AlCl3-induced AD like pathology.

The Effect of a Continuous Training on Necrosis and Apoptosis Changes in the Hippocampus of Diabetic Rats

Introduction: Diabetes is associated with different neurological disorders in the nervous system that will eventually lead to cell damage. The previous studies have shown the beneficial effects of exercise on brain damage caused by diabetic neuropathy in animal models. In the present study, the effect of aerobic exercise training on cell death in the hippocampal CA1 area neurons in diabetic male rats was investigated. Materials & methods: 21 adult male Wistar rats (weighing 260-300 g) were purchased from Tehran Pasteur Institute and were randomly divided into three groups: sham group, diabetic group and diabetic + exercise training group (7 rats per group). Diabetes was induced intraperitoneally streptozotocin (STZ) administration at the dose of 60mg/kg. The diabetes criterion was the blood glucose level higher than 250 mg/dl. One week after induction of diabetes, the rats in exercise training group were trained to run on a treadmill 5 days a week for 4 weeks. Necrotic cell death was detected by Nissl staining and apoptosis was detected by TUNEL staining. Findings: The results showed that aerobic exercise training significantly reduced the diabetes-induced necrotic cell death (p<0.01) and apoptosis (p<0.05) in the hippocampal CA1 area neurons. Discussion & conclusions: This study showed that aerobic exercise training has neuroprotective effects against diabetic neuropathy. This neuroprotective mechanism of exercise can be an effective way to reduce cerebral complications of diabetes.n

Targeting the innate repair receptor to treat neuropathy.

The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the β-common (CD131) receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a β-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D) mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies.

Mechanisms of the gabapentinoids and α 2 δ-1 calcium channel subunit in neuropathic pain.

The gabapentinoid drugs gabapentin and pregabalin are key front‐line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ‐1 and α 2 δ‐2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α 2 δ‐1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α 2 δ‐1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.

Glucotoxic Mechanisms and Related Therapeutic Approaches.

Neuropathy is the earliest and commonest complication of diabetes. With increasing duration of diabetes, frequency and severity of neuropathy are worsened. Long-term hyperglycemia is therefore implicated in the development of this disorder. Nerve tissues require glucose energy to function and survive. Upon excessive glucose entry into the peripheral nerve, the glycolytic pathway and collateral glucose-utilizing pathways are overactivated and initiate adverse effects on nerve tissues. During hyperglycemia, flux through the polyol pathway, formation of advanced glycation end-products, production of free radicals, flux into the glucosamine pathway, and protein kinase C activity are all enhanced to negatively influence nerve function and structure. Suppression of these aberrant metabolic pathways has succeeded in prevention and inhibition of the development of neuropathy in animal models with diabetes. Satisfactory results were not attained, however, in patients with diabetes and further clinical trials are required. In this review, the author summarizes the hitherto proposed theories on the pathogenesis of diabetic neuropathy related to glucose metabolism and future prospects for the effective treatment of neuropathy.

Inflammation: Therapeutic Targets for Diabetic Neuropathy

There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials.

Abstract P1-15-07: Ixabepilone-associated peripheral neuropathy in metastatic breast cancer patients and its effects on the ultrastructure of neurons

Abstract Background: Peripheral neuropathy is a dose-limiting toxicity of most microtubule-stabilizing chemotherapeutic agents. Ixabepilone, a semisynthetic analog of the natural epothilone B, has activity in a wide range of tumors including taxane-resistant disease. In this study, we sought to understand the effect of ixabepilone on the development of peripheral neuropathy both clinically and its effect at the ultrastructural level of the peripheral nerves and circulating factors over time. Parallel studies in animal models of neuropathy were performed at the same time (Proc AACR 2010 Abstract 4184). Methods: This open-label, non-randomized phase II study enrolled 14 patients with metastatic breast cancer. Ixabepilone was administered by 2 schedules: the FDA approved dose of 40 mg/m2 every 3 weeks (q3w) and 16 mg/m2 on day 1, 8, and 15 of a 28-day cycle (weekly). Five controls, 2 with residual taxane-associated peripheral neuropathy and 3 with no prior chemotherapy or peripheral neuropathy, were also accrued. The primary objectives were to characterize the natural history of ixabepilone-associated peripheral neuropathy using the Total Neuropathy Score Clinical (TNSc) assessment tool prior to each cycle and to correlate changes in the ultrastructure of dermal myelinated nerve fibers via a 3 mm punch biopsy of an area 10 cm above the lateral malleolus every 2 cycles with electron microscopy (EM), as well as circulating factors (both inflammatory and neurotrophic) considered to be important in the pathogenesis of chemotherapy-induced peripheral neuropathy. Secondary objectives included progression-free survival (PFS) and non-neurologic toxicity. Results: 14 patients were enrolled and were equally divided between the 2 schedules of ixabepilone chemotherapy. There were no differences in baseline characteristics between the two groups. Mean age was 54 years (range 32–71). Mean number of previous chemotherapy regimens was 3.5 (range 0–8). 57% of patients had received a taxane in the adjuvant setting and 64% in the metastatic setting. The mean neuropathy score (TNSc) at baseline was 4.6 (range 1–11). At a mean cumulative dose of 185 mg/m2, the TNSc with ixabepilone q3w schedule was 3.7 points higher/worse (95% CI: 2.2–5.3, p = 0.03) than the mean score observed in patients on the weekly schedule. The sensory component was most significantly affected, predominantly numbness. In 3 patients, the chemotherapy schedule was changed from every 3 weeks to weekly due to &amp;gt; grade 2 toxicity at a mean cumulative dose of 107 mg/m2, and TNSc decreased/improved by 2.7 points. PFS in patients on q3w ixabepilone was 133 days (range 28–280) and in patients on weekly ixabepilone was 179 days (range 66–336), nonsignificant. Evaluation of EM and circulating factors is ongoing. Conclusions: Weekly ixabepilone appears to have a more favorable neurotoxicity profile compared to the standard q3w schedule. Integration of the EM data and the circulating factor data are underway and will be presented. Ixabepilone-associated peripheral neuropathy may improve in patients switched to weekly ixabepilone without compromising efficacy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-07.

Acute behavioural responses to tail docking in piglets – Effects of increasing docking length?

Abstract Background and aim Tail docking has been suggested as an animal model of neuropathy and pain based on findings of relations between the degree of neuroma formation and the docking length. We examined effects of docking length on behaviour of piglets during and 6 h after tail docking. Methods Piglets were tail docked 2–4 d post-partum. We used 53 piglets and four treatments: intact (I), removal of either 25 (Q), 50 (H) or 75% (T) of the tail. The piglets were kept with sow and littermates under production conditions, and docked using a gas-heated instrument. Behaviour was observed during docking and for the following 6 h. Results Tail docking led to behavioural changes, the magnitude of which to some extend depended on docking length. Increased docking length led to increased intra-procedural vocalization score (0, 0.6 ± 0.2, 1.4 ± 0.2 and 1.4 ± 0.2 for I, Q, H and T, respectively, P&lt;0.001). In the initial 6h, increased docking length led to increased time spent in the heated creep area (2 ± 1%, 15 ± 6%, 18±8% and 30±6% for I, Q, H and T, respectively; P&lt;0.05). Piglet posture was affected as well, showing that increased docking length led to decreased lying (71 ± 2%, 68 ± 2%, 61 ± 2% and 61 ± 2% for I, Q, H and T, respectively, P&lt;0.01) and increased time spent active (24 ± 2%, 23 ± 2%, 32 ± 2% and 30 ± 3% for I, Q, H and T, respectively, P&lt; 0.05). Pain specific behaviours such as trembling or tail flicking were registered and occurred in 5 ± 1% and 9 ± 1% of observations. However, no effects of docking length could be shown. Conclusions Piglets responded behaviourally to tail docking. Increasing docking length led to increased pain responses such as intra-procedural vocalizations, hiding behaviour and reduced rest, indicative of increased pain. These results confirm earlier reports suggesting that tail docking might be suitable as an animal model for neuropathy and pain.

Recent advances in the management of diabetic distal symmetrical polyneuropathy.

There is now little doubt that poor blood glucose control is an important risk factor for the development of diabetic peripheral neuropathy (DPN). Furthermore, traditional cardiovascular risk factors for macrovascular disease appear to be associated with an increased risk of DPN. The recently established International Expert Group on Diabetic Neuropathy has recommended new criteria for the diagnosis of DPN in the context of clinical and research settings. Studies in experimental diabetes examining the pathogenesis of DPN have identified a number of metabolic abnormalities including polyol pathway hyperactivity, increased advanced glycation end-point formation, alterations in the protein kinase C beta pathway through diacylglycerol and oxidative stress. There is now strong evidence implicating nerve ischemia as the cause of DPN. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. These endoneurial microvascular changes strongly correlate with clinical severity and the degree of nerve-fiber pathology. Unfortunately, many compounds that have been effective in animal models of neuropathy have not been successful in human diabetic neuropathy. The only compounds found to be efficacious in human diabetic neuropathy, and are in clinical use, are the anti-oxidant, α-lipoic acid and the aldose reductase inhibitor, epalrestat. Overall, the evidence emphasizes the importance of vascular dysfunction, driven by metabolic change, in the etiology of DPN, and highlights potential therapeutic approaches. Epidemiological data on diabetic painful neuropathic pain (DPNP) are limited. In one population-based study, the prevalence of DPNP, as assessed by a structured questionnaire and examination, was estimated at 16%. It was notable that, of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain. Thus, despite being common, DPNP continues to be underdiagnosed and undertreated. Pharmacological treatment of DPNP include tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the anti-oxidant α-lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin and so on. Management of the patient with DPNP must be tailored to individual requirements and will depend on the presence of other comorbidities. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00083.x).

Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75(NTR). During retinal injury, endogenous NGF, TrkA, and p75(NTR) are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75(NTR) affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75(NTR) agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75(NTR) action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-α and α(2)-macroglobulin. Antagonists of p75(NTR) inhibit TNF-α and α(2)-macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.

The ventral caudal nerve: a physiologic‐morphometric study in three different rat strains

The caudal nerve is often used for investigating alterations in nerve conduction velocity (NCV) to determine the presence of peripheral neuropathy in animal models. In the present study, the rat caudal nerve of two outbred strains (Wistar Hannover and Sprague-Dawley) and one inbred strain (Fischer-344) was analyzed with regard to morphologic, morphometric, and physiologic features. In all three strains, we calculated the myelinated fiber diameter, myelinated axon diameter, and g-ratio in the proximal caudal nerve and correlated these results with NCV in the distal caudal nerve. Although the caudal nerves were morphologically similar in the three rat strains, a significant difference was present morphometrically: there was a statistically significant increase in the g-ratio associated with a reduction in myelinated fiber diameter in Fischer-344 rats vs. Wistar Hannover and Sprague-Dawley animals (p < 0.01). However, there was no significant difference in NCV results in the distal caudal nerve. The present study adds morphologic and morphometric information on the rat caudal nerve that might be useful for a better interpretation of studies involving this nerve and its pathological changes in experimental models of peripheral neuropathies.

Differential pharmacological modulation of the spontaneous stimulus-independent activity in the rat spinal cord following peripheral nerve injury

Peripheral nerve injury is a significant clinical problem that is often difficult to treat. The major clinical symptoms are numbness, tactile and cooling allodynia, hyperalgesias as well as ongoing pain. In animal models of neuropathy, abnormal responses to applied (or evoked) stimuli can be gauged, but spontaneous pain, a major clinical issue, has proved very difficult to assess. In neuropathic animals, spinal neuronal hyperexcitability indicative of peripheral and central changes with high levels of spontaneous neuronal firing has been reported. This latter stimulus-independent firing of sensory neurones may be a measure related to ongoing pain. Two weeks after L5/6 spinal nerve ligation, deep dorsal horn neurones were recorded in halothane-anesthetized rats. The majority of neurones in neuropathic rats showed increased levels of spontaneous firing with irregular firing patterns. We examined and compared the effects of 5 centrally acting pharmacological agents: morphine (i.t. or i.v.), gabapentin, ketamine, memantine and mepyramine on stimulus-independent neuronal firing. This ongoing activity showed high sensitivity to gabapentin (s.c.) and morphine (i.t.) administration, being significantly reduced in a dose-dependent manner. Morphine administered via the systemic route produced modest but non-significant reductions of spontaneous activity. The two NMDA receptor antagonists, ketamine and memantine, and the histamine H 1 receptor antagonist, mepyramine, produced minor effects at doses known to be effective on stimulus evoked measures of deep dorsal horn neurones. This may form an electrophysiological basis for the efficacy of gabapentin and spinal morphine on ongoing pain in patients with peripheral neuropathy.