RESUMEN
We have recently demonstrated that prosaposin is a neurotrophic and myelinotrophic factor with the active trophic sequence located at the N-terminal region of the saposin C domain. There are also reports that prosaposin mRNA is increased distal to a physical nerve injury and that exogenous prosaposin treatment induces subsequent neuronal sprouting, suggesting involvement in repair processes. In the present study, we show that prosaposin mRNA is significantly (p < 0.05) elevated in the peripheral nerve of streptozotocin-diabetic rats, a model of insulin-deficient diabetes in which nerve injury arises from the metabolic trauma of hyperglycemia and its consequences. A 14 amino acid peptide derived from the neurotrophic region of prosaposin prevented the development of deficits in both large and small fiber function caused by diabetes in rats. The dose-dependent prevention of nerve conduction slowing by TX 14(A) was accompanied by preservation of axonal caliber and sodium-potassium ATPase activity, while prevention of thermal hypoalgesia was associated with attenuation of the decline in nerve substance P levels. It is concluded that nerve subject to the metabolic injury of uncontrolled diabetes responds by increasing prosaposin gene expression, and that prosaposin-derived neurotrophic peptides may provide a novel therapeutic approach to treatment of diabetic and other peripheral neuropathies.
Asunto(s)
Neuropatías Diabéticas/fisiopatología , Glicoproteínas/genética , Precursores de Proteínas/genética , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Neuropatías Diabéticas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica , Conducción Nerviosa , Ratas , Ratas Sprague-Dawley , Saposinas , Nervio Ciático/fisiopatologíaRESUMEN
The effects of hindlimb temperature on sciatic nerve and skeletal muscle laser Doppler vascular conductance (LDVC) were assessed in anesthetized control and streptozotocin (STZ)-diabetic rats. With core temperature at 37 degrees C and exposed hindlimb temperature at 32 degrees C, nerve LDVC was significantly lower in rats after 8 weeks of STZ diabetes than in age-matched control rats. Subsequent warming of the exposed hindlimb of control rats from 32 degrees C to 37 degrees C significantly decreased nerve LDVC by 41% and increased muscle LDVC by 48%. Because nerve LDVC was unchanged by hindlimb warming in STZ-diabetic rats, there was no significant difference between control and diabetic nerve LDVC at 37 degrees C. In a second study, after 6 weeks of STZ diabetes, changes from control nerve LDVC were shown to depend on temperature rather than the duration of surgical exposure. These findings emphasize that information about hindlimb temperature is a prerequisite for interpreting the effects of experimental diabetes on hindlimb nerve blood flow.
Asunto(s)
Temperatura Corporal/fisiología , Diabetes Mellitus Experimental/fisiopatología , Hemodinámica , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/inervación , Nervio Ciático/irrigación sanguínea , Nervio Ciático/fisiopatología , Animales , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Miembro Posterior/irrigación sanguínea , Miembro Posterior/inervación , Miembro Posterior/fisiología , Flujometría por Láser-Doppler , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Nervio Ciático/fisiologíaRESUMEN
Multiple Renaut bodies were identified by light microscopy in the biopsied common peroneal nerve of a dog with generalized neuropathy, hypothyroidism and a history of cutaneous mastocytosis. In addition, numerous granulated cells were associated with most of the Renaut bodies. Electron microscopic examination confirmed these to be mast cells, both central and peripheral to Renaut bodies, a phenomenon never previously reported. Endoneurial fibrosis, myelinated fiber loss, as well as evidence of axonal degeneration, demyelination and remyelination were observed. 'Vacuolation' of endoneurial fibroblasts was also present. The location of these Renaut bodies in the common peroneal nerve, and the absence of any documented or expected nerve compression, implicates other etiological factors. These observations are the first to report an association between mast cells and Renaut bodies. It is possible that mast cells, at least in this case, are involved in the formation of Renaut bodies.
Asunto(s)
Enfermedades de los Perros/inmunología , Cuerpos de Inclusión/inmunología , Mastocitosis/veterinaria , Enfermedades del Sistema Nervioso Periférico/veterinaria , Nervio Peroneo/patología , Animales , Biopsia , Enfermedades de los Perros/patología , Perros , Fibroblastos/patología , Fibroblastos/ultraestructura , Fibrosis , Hipotiroidismo/inmunología , Hipotiroidismo/patología , Hipotiroidismo/veterinaria , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/ultraestructura , Masculino , Mastocitos/inmunología , Mastocitos/ultraestructura , Mastocitosis/inmunología , Mastocitosis/patología , Microscopía Electrónica , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/patología , Nervio Peroneo/inmunologíaRESUMEN
In an initial study, the effects of galactose intoxication on nerve laser Doppler blood flow (NLDF) and nerve conduction velocity (NCV) were assessed after 1-16 weeks of galactose feeding in pentobarbital-anesthetized rats. NLDF was not significantly changed at any time point. NCV was significantly reduced after 16, but not 1 or 4, weeks of galactose feeding. In a second study, NLDF was not significantly changed by 4 weeks of galactose intoxication, but streptozotocin-diabetic NLDF was significantly reduced compared to both control (P<0.001) and galactose-intoxicated rats (P<0.05). Compared to control animals, sciatic motor NCV was significantly (P<0.001) reduced in the galactose group, while sciatic and saphenous sensory NCVs were not significantly changed. In the streptozotocin-diabetic rats, motor and sensory NCVs were all significantly reduced (P<0.001). In contrast to the NCV findings, mean caliber of myelinated axons in both the saphenous and sciatic nerves was reduced in galactose-intoxicated, but not streptozotocin-diabetic rats. The observed sequence of changes associated with these two models of diabetic neuropathy is not consistent with the proposed roles of ischemia and axonal dwindling in the reported nerve conduction deficits.
Asunto(s)
Axones/fisiología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Conducción Nerviosa/fisiología , Animales , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Diabetes Mellitus Experimental/inducido químicamente , Femenino , Galactosa , Frecuencia Cardíaca/fisiología , Flujometría por Láser-Doppler , Fibras Nerviosas/fisiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/citología , Nervio Ciático/fisiologíaRESUMEN
The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections. After 2 months, sciatic and saphenous sensory nerve conduction velocity (SNCV) and sciatic motor nerve conduction velocity (MNCV) were measured and the sciatic, sural, peroneal and saphenous nerves and dorsal and ventral roots processed for light microscopy. Treatment of control animals with NT-3 had no effect on any functional or structural parameter. Compared to control values, galactose feeding induced a sensory and motor nerve conduction deficit and a reduction in axonal caliber. Treatment with 5 and 20 mg/kg NT-3 ameliorated deficits in sciatic and saphenous SNCV in galactose-fed rats but had no effect on the MNCV deficit. NT-3 treatment also attenuated the decrease in mean axonal caliber in the dorsal root and sural nerve but not in the saphenous nerve, ventral root and peroneal nerve. These observations show that NT-3 can selectively attenuate the sensory conduction deficit of galactose neuropathy in a dose-dependent manner that depends only in part on restoration of axonal caliber of large-fiber sensory neurons.
Asunto(s)
Galactosa/toxicidad , Factores de Crecimiento Nervioso/farmacología , Conducción Nerviosa/efectos de los fármacos , Raíces Nerviosas Espinales/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Animales , Axones/efectos de los fármacos , Axones/fisiología , Femenino , Alimentos Fortificados , Galactosa/administración & dosificación , Galactosa/antagonistas & inhibidores , Humanos , Inyecciones Subcutáneas , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Neuronas Motoras/fisiología , Factores de Crecimiento Nervioso/administración & dosificación , Factores de Crecimiento Nervioso/fisiología , Conducción Nerviosa/fisiología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/patología , Neuronas Aferentes/fisiología , Neurotrofina 3 , Nervio Peroneo/efectos de los fármacos , Nervio Peroneo/fisiología , Nervio Peroneo/fisiopatología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Nervio Ciático/fisiopatología , Raíces Nerviosas Espinales/patología , Raíces Nerviosas Espinales/fisiología , Nervios Espinales/fisiología , Nervios Espinales/fisiopatologíaRESUMEN
Motor and sensory nerve conduction velocities (MNCV and SNCV) were reduced in the sciatic nerve of rats after 4 weeks of untreated streptozotocin-induced diabetes, and declined further during the following 4 weeks. Treating diabetic rats with the novel peptide HP228 had no effect on the decline of MNCV after the first 4 weeks of diabetes but attenuated the decline in SNCV. HP228 treatment also prevented any further decline in MNCV or SNCV between weeks 4 and 8 of diabetes. Consequently, at the conclusion of the study, the nerve conduction velocities (NCVs) in treated rats were significantly (both P < .001) higher than in untreated diabetic rats. Reduced nerve homogenate Na+,K+-adenosine triphosphatase (ATPase) activity in diabetic rats was significantly (P < .05) increased by HP228 but remained significantly (P < .05) lower than in untreated controls. HP228 treatment also reduced nerve Na+,K+-ATPase activity of control rats compared with untreated controls (P < .05). There was no effect of HP228 on the hyperglycemia, nerve polyol accumulation, myo-inositol depletion, reduced nerve laser Doppler blood flow, thermal hypoalgesia, or reduced mean axonal caliber in diabetic rats or on any of these parameters in control rats. These data demonstrate that a novel peptide may protect against the slowing of nerve conduction in prolonged diabetes and that the mechanism of action is unrelated to aldose reductase inhibition, prevention of nerve ischemia, or axonal atrophy. HP228 may prove a potential therapeutic agent for the treatment of prolonged diabetic neuropathy.
Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Animales , Axones/fisiología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Femenino , Neuronas Motoras/fisiología , Conducción Nerviosa/fisiología , Neuronas Aferentes/fisiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Nervio Ciático/fisiopatología , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
The effects of wire grates on nerve injury and recovery were examined in rats housed in cages with sawdust-covered solid flooring. For the first 3 weeks of the study, 20 rats were housed on sawdust alone and 20 rats were housed in cages with wire grates placed over the sawdust. For the remaining 9 weeks, 10 animals housed on sawdust had wire grates added to their cages, while grates were removed from the cages of 10 animals. The effects of tactile stimulation on hindpaw plantar skin was measured weekly using the Von Frey filament test. Intraepidermal innervation using PGP 9.5 immunostaining and plantar nerve histology were assessed at the end of the 12-week study. After just 1 week on grates, hindpaw withdrawal thresholds were already markedly decreased and remained low until the grates were removed at 3 weeks. Thresholds returned to normal by 4 weeks after removal of the grates. Wire grates also induced increases in PGP 9.5 immunoreactive intraepidermal fine nerve endings that were normalized after grate removal. Demyelination, Wallerian degeneration and Renaut bodies were induced in the medial plantar nerve in rats housed in cages with wire-grate flooring. Nerve injury was largely resolved after 9 weeks on sawdust flooring. These data demonstrate that wire grates rapidly induce hindpaw tactile hyperesthesia and plantar neuropathy in rats and emphasize a risk of using wire-grate cage flooring in studies assessing hindlimb function and structure.
Asunto(s)
Epidermis/inervación , Pie/inervación , Hiperestesia/fisiopatología , Traumatismos de los Nervios Periféricos , Tacto/fisiología , Animales , Femenino , Miembro Posterior , Vivienda para Animales , Inmunohistoquímica , Proteínas del Tejido Nervioso/análisis , Presión , Ratas , Ratas Sprague-Dawley , Tioléster Hidrolasas/análisis , Ubiquitina TiolesterasaRESUMEN
In summary, mast cell interactions in the nervous system are relevant to both physiological processes (i.e. reproduction) and pathologic states (i.e. inflammatory demyelination, painful disorders, toxic and metabolic disease, and tumor angiogenesis). Their physiologic roles may contribute to gender-related vulnerability to inflammatory disease and may modulate sensitivity to pain. Mast cells are universally involved in tissue repair and they release and respond to trophic factors such as NGF. These cells also produce and react to cytokines, and thus appear to play a role in tissue degeneration as well as repair. In certain neurological diseases, i.e. multiple sclerosis and Guillain-Barré syndrome, the ability of mast cell proteases to degrade specific myelin proteins suggests that these cells are agents, rather than bystanders, in the demyelinative process. Even more intriguing is their recently identified capacity to process bacterial antigen as efficiently as activated macrophages, suggesting that a more critical role than previously suspected might be considered for mast cells in CNS and PNS demyelination. In experimental metabolic disorders such as galactose intoxication and thiamine deficiency, mast cells appear to play a pathogenic role. Thus, in galactose intoxication, altered BNB vascular permeability occurs in conjunction with mast cell proliferation and degranulation, while in thiamine deficiency, increased histamine levels have been reported in the rat thalamus (79) and are associated with cell death and proliferation as well as mast cell degranulation (Powell and Langlais, unpublished observations). Structural interactions between mast cells and a variety of other cells have been observed, as well as close approximation of mast cells to nerve endings in tissues in which mast cells are especially active. Due to their paracrine nature, mast cells can modulate events in their microenvironment through explosive degranulation, piecemeal degranulation, or "transgranulation" as they insert granules into neighboring cells. Lastly, these cells play specific roles in reparative processes, e.g. angiogenesis, and are active in neoplastic states, including von Recklinghausen's disease (neurofibromatosis). Their involvement may have been underestimated in neuropathological studies, to date, by a reliance on staining techniques that are inadequate for identifying degranulated and therefore activated mast cells (4). More exacting histochemical and immunostaining procedures will help to fully realize the extent of their participation in physiological and pathological processes.
Asunto(s)
Mastocitos/fisiología , Enfermedades del Sistema Nervioso/fisiopatología , Fenómenos Fisiológicos del Sistema Nervioso , Animales , Enfermedades Desmielinizantes/fisiopatología , Estrógenos/fisiología , Neovascularización Patológica/fisiopatología , Factores de Crecimiento Nervioso/fisiología , Dolor/fisiopatología , RatasRESUMEN
The role of body and hindlimb temperature in the control of blood flow in nerve and muscle was assessed by laser Doppler flowmetry. Following surgical exposure of nerve, initial measurements were taken for 5 min at hindlimb temperatures of 30-31 degrees C. A second set of identical measurements was then made either with or without warming to 37 degrees C. Without warming, nerve laser Doppler flow (NLDF) increased by 14.5+/-3.2% (mean+/-SEM) but, with warming, decreased by 40.9+/-8.2%. In contrast, adduccamerontor magnus muscle laser Doppler flow (MLDF) decreased without warming (14.7+/-1.0%) and increased with warming (20.4+/-12.8%). Because blood pressure was not significantly altered by changes in hindlimb temperature, the patterns of changes in vascular conductance (laser Doppler flow/blood pressure) were not significantly different from that seen with NLDF and MLDF. Thus, warming to physiological temperatures was associated with decreased NLDF and vascular conductance and increased MLDF and vascular conductance. These data may have implications for the interpretation of nerve blood flow data obtained at different hindlimb temperatures.
Asunto(s)
Temperatura Corporal/fisiología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiología , Nervio Ciático/fisiología , Adyuvantes Anestésicos/farmacología , Animales , Femenino , Miembro Posterior , Hipotermia/fisiopatología , Flujometría por Láser-Doppler , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Pentobarbital/farmacología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Tiopental/análogos & derivados , Tiopental/farmacologíaRESUMEN
Reduced nerve conduction velocity (NCV) in experimental diabetes can be prevented by evening primrose oil (EP), which is rich in gamma-linolenic acid (GLA). This study examined the efficacy of natural GLA sources, blackcurrant (BC), borage (BO) and fungal (FU) oils, compared with EP, in correcting motor and sensory NCV deficits in streptozotocin-diabetic rats, and any potential contribution of thromboxane (TX) A2 synthesis using the TX antagonist, ZD1542, alone and jointly with GLA-rich oils. Sciatic motor NCV, 20% reduced by 8 weeks of diabetes, was partially (16%) corrected by 2 weeks ZD1542 treatment. 1% BC, BO, FU and EP dietary supplementation caused 11%, 32%, 41% and 53% NCV ameliorations, respectively. A 2% EP diet, more closely matching the GLA intake from the other oils, caused 67% correction. Joint oil/ZD1542 treatment produced further motor NCV improvements for BC and, particularly, BO. A 13% sensory saphenous NCV deficit in diabetic rats was ameliorated by 31%, 24%, 49%, 81%, 70% and 94% for ZD1542, BC, BO, FU, EP and 2% EP, respectively. Joint ZD1542-oil treatment further improved NCV, particularly for BO. Therefore, efficacy against experimental diabetic neuropathy is not predictable from the GLA content of natural oils, EP consistently outperforming BC, BO and FU. Increased TXA2 with diabetes made a minor contribution to NCV deficits, but blockade improved the response to BO.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Dioxanos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Conducción Nerviosa/efectos de los fármacos , Aceites de Plantas/uso terapéutico , Piridinas/uso terapéutico , Ácido gammalinolénico/uso terapéutico , Animales , Glucemia/análisis , Peso Corporal , Diabetes Mellitus Experimental/fisiopatología , Quimioterapia Combinada , Ácidos Grasos Esenciales/uso terapéutico , Ácidos Linoleicos , Masculino , Oenothera biennis , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Estreptozocina , Tromboxano-A Sintasa/antagonistas & inhibidoresRESUMEN
The main aim was to investigate whether 1 month of aldose reductase inhibitor treatment could correct a deficit in sciatic nerve nutritive blood flow following 1 month of untreated streptozotocin-induced diabetes in rats. Treatment was with two doses of WAY-121,509, both of which completely blocked neuronal sorbitol accumulation. The high dose fully corrected a motor conduction velocity deficit, whereas the low dose caused 51.3% amelioration. Nutritive endoneurial blood flow, monitored by hydrogen clearance, was 43.4% reduced after 1 month of diabetes. This was completely corrected by the high dose of WAY-121,509. In addition, vascular conductance was supranormal and there was a decrease in arteriovenous shunt flow. Low dose treatment caused a 55.6% improvement of the nutritive endoneurial blood flow deficit, paralleling the conduction velocity effect. WAY-121,509 did not alter nerve perfusion in nondiabetic rats. Data from multiple sciatic nerve penetrations by oxygen sensitive microelectrodes revealed a 42.0% deficit in mean endoneurial oxygen tension with diabetes, whereas tensions were in the nondiabetic range for high dose WAY-121,509 treatment. Thus, the data highlight neurovascular actions of aldose reductase inhibition, and suggest that neuronal polyol pathway metabolite levels are a poor predictor of functional efficacy.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Conducción Nerviosa/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Aldehído Reductasa/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Fructosa/metabolismo , Inositol/metabolismo , Masculino , Oxígeno/metabolismo , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Nervio Ciático/irrigación sanguínea , Sorbitol/metabolismoRESUMEN
Increased generation of reactive oxygen species, coupled with impaired endogenous scavenging mechanisms, plays a prominent role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. We examined the efficacy of the natural anti-oxidants vitamins C, E and beta-carotene in preventing nerve conduction and nutritive blood flow deficits in streptozotocin-diabetic rats. One month of diabetes caused a 19.1% reduction in sciatic motor conduction velocity (p < 0.001). This was approximately prevented 80-90% by high-dose (1000 mg.kg-1.day-1) vitamin E and beta-carotene treatments (p < 0.001). Vitamin C had lesser effects; the maximum protection found for motor conduction velocity was 36% using a dose of 150 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1) vitamin C had a lesser effect on conduction than intermediate doses. Joint vitamin C and lower dose (500 mg.kg-1.day-1) vitamin E treatment had a predominantly additive preventive effect against nerve dysfunction. Resistance to hypoxic conduction failure for sciatic nerve in vitro was markedly increased by diabetes and this remained relatively unaffected by treatment. Sciatic nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was reduced 46.1% by 1 month of diabetes (p < 0.001). This was prevented to the extent of 87%, 36% and 98% by vitamins E, C and beta-carotene, respectively (p < 0.01). These data emphasize the role of oxidative stress in the development of early neurovascular changes in experimental diabetes and show that naturally available scavengers have a neuroprotective action.
Asunto(s)
Antioxidantes/farmacología , Diabetes Mellitus Experimental/fisiopatología , Conducción Nerviosa/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Potenciales de Acción , Animales , Ácido Ascórbico/farmacología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Carotenoides/farmacología , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres , Masculino , Estrés Oxidativo/efectos de los fármacos , Nervios Periféricos/fisiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Vitamina E/farmacología , beta CarotenoRESUMEN
L-Carnitine metabolism is abnormal in diabetes mellitus, and treatment with acetyl-L-carnitine (ALC) improves the function of cardiac muscle, retina, and peripheral nerve in experimental models. The aim was to compare the effects of ALC and proprionyl-L-carnitine (PLC) on motor and sensory nerve conduction in streptozotocin-diabetic rats and to ascertain whether their action could be mediated by a vascular mechanism. ALC and PLC treatment for 2 months after diabetes induction attenuated the development of sciatic motor nerve conduction velocity (NCV) deficits by 59.4% +/- 4.4% and 46.9% +/- 3.2%, respectively. There was a similar level of protection for sensory saphenous NCV (42.9% +/- 6.6% and 47.8% +/- 6.0%, respectively). Neither ALC nor PLC prevented the development of resistance to hypoxic conduction failure (RHCF) in sciatic nerve from diabetic rats. A 46.5% +/- 3.4% deficit in sciatic endoneurial blood flow, measured by microelectrode polarography and hydrogen clearance, in diabetic rats was partially prevented by both ALC (48.7% +/- 6.4%) and PLC (69.4% +/- 10.1%). ALC had no significant effect on blood flow in nondiabetic rats. Thus, the data show that these L-carnitine derivatives have a similar efficacy in preventing nerve dysfunction, which depends on a neurovascular action.
Asunto(s)
Acetilcarnitina/farmacología , Carnitina/análogos & derivados , Diabetes Mellitus Experimental/fisiopatología , Nervios Periféricos/irrigación sanguínea , Nervios Periféricos/fisiopatología , Acetilcarnitina/uso terapéutico , Potenciales de Acción , Animales , Velocidad del Flujo Sanguíneo , Glucemia/metabolismo , Peso Corporal , Carnitina/farmacología , Carnitina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Cinética , Masculino , Conducción Nerviosa/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Ciático/irrigación sanguínea , Nervio Ciático/fisiopatologíaRESUMEN
The aim was to ascertain whether the ability of evening primrose oil (EPO) treatment to correct peripheral nerve dysfunction in streptozotocin-diabetic rats depends on a gamma-linolenic acid (GLA)-containing triglyceride constituent, di-linolein mono-gamma-linolenate (DLMG). A second objective was to investigate whether the triglyceride conformation of GLA affects efficacy, using tri-gamma-linolenate (TGLA), which is not present in EPO. Third, we examined the actions of these omega-6 essential fatty acid-containing oils on sciatic nerve blood flow to establish a common mechanism. After 6 weeks of diabetes, sciatic motor nerve conduction velocity (NCV) was 21% reduced. EPO treatment caused dose-dependent increases in NCV that reached asymptote within 7 days. DLMG and TGLA, at doses matched for GLA content, had effects indistinguishable from those of EPO. Sciatic blood flow, 47.2% reduced by diabetes, was partially normalized by EPO, DLMG and TGLA. In contrast, sunflower oil (which does not contain GLA) did not alter NCV or blood flow. The data therefore provide strong evidence that DLMG is the active component of EPO and suggest that correction of nerve dysfunction involves a vascular action. The precise triglyceride configuration of GLA does not appear crucial to its effects in experimental diabetic neuropathy.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Grasas Insaturadas en la Dieta/farmacología , Ácidos Grasos Esenciales/farmacología , Conducción Nerviosa/efectos de los fármacos , Triglicéridos/farmacología , Ácido gammalinolénico/farmacología , Animales , Relación Dosis-Respuesta a Droga , Flurbiprofeno/farmacología , Ácidos Linoleicos , Masculino , Oenothera biennis , Aceites de Plantas , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Nervio Ciático/efectos de los fármacos , EstreptozocinaRESUMEN
Abnormal vascular endothelium function may contribute to the reduced nerve perfusion implicated in the aetiology of neuropathy in diabetes mellitus. The aim was to test the hypothesis that a powerful vasoconstrictor, endothelin-1, could be involved in nerve dysfunction in streptozotocin-diabetic rats. After 6 weeks of untreated diabetes, rats were implanted with osmotic minipumps which continuously delivered the endothelin-1 antagonist, BQ-123, to the circulation via a jugular vein cannula. Sciatic motor conduction velocity, monitored serially, was increased after 4 days, treatment (p = 0.028), and reached asymptote by 9-11 days (p = 0.0001), when the degree of amelioration was approximately 60% of the initial diabetic deficit. Treatment of non-diabetic rats for 13 days with BQ-123 had no significant effect on motor conduction velocity. Sensory saphenous nerve conduction velocity was measured acutely after 20 days, BQ-123 treatment. The amelioration of a sensory deficit was approximately 80% (p < 0.001); the resultant conduction velocity value was not significantly different from that of a non-diabetic control group. After 20 days, treatment, sciatic nutritive endoneurial blood flow was measured by microelectrode polarography and hydrogen clearance. A 48% deficit with untreated diabetes (p < 0.001) was 64% ameliorated by BQ-123 treatment (p < 0.001). In non-diabetic rats, BQ-123 treatment had no effect on blood flow. We conclude that endothelin-1 does not seem to be involved in the control of nerve blood flow in non-diabetic rats; however, it makes a major contribution to the perfusion deficit in experimental diabetes. This has deleterious consequences for nerve conduction, and it is possible that endothelin-1 receptor blockade may have therapeutic potential in diabetic patients.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/fisiopatología , Neuropatías Diabéticas/fisiopatología , Antagonistas de los Receptores de Endotelina , Endotelinas/fisiología , Neuronas Motoras/fisiología , Péptidos Cíclicos/farmacología , Análisis de Varianza , Animales , Endotelinas/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Masculino , Neuronas Motoras/efectos de los fármacos , Conducción Nerviosa/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiología , Nervios Periféricos/fisiopatología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Nervio Ciático/fisiopatología , Factores de TiempoRESUMEN
We examined the effects of aldose reductase inhibition on nerve biochemistry and function, blood flow and endoneurial oxygenation in experimental diabetes mellitus. After 1 month untreated diabetes in rats, treatment with the novel sulphonylnitromethane aldose reductase inhibitor, ZENECA ZD5522, prevented a progressive increase in sciatic nerve resistance to hypoxic conduction failure (p < 0.05). Motor conduction velocity deficits after 4 months untreated diabetes were rapidly returned to normal within 12 days (p < 0.0001) by ZD5522 treatment. Following 2-months untreated diabetes, examination of 1 month ZD5522 treatment dose-response relationships for correction of nerve sorbitol and fructose accumulations and reduction in myo-inositol concentration, sciatic motor and saphenous sensory conduction velocity and sciatic blood flow by laser-Doppler flowmetry revealed poor agreement between nerve function and biochemical indices. In addition, polyol accumulation differed between sciatic and saphenous nerves, the latter showing ten-fold lower sorbitol concentrations. Laser-Doppler blood flow was 60% decreased by untreated diabetes (p < 0.001) and there was a strong correlation between ZD5522-mediated increases in blood flow and conduction velocity (p < 0.0001). Measurement of nutritive endoneurial blood flow by microelectrode polarography and hydrogen clearance showed 44% and 45% deficits for 1 and 2 months untreated diabetes (p < 0.001) that were prevented by ponalrestat and ZD5522 treatments, respectively. In contrast, 2 months myo-inositol treatment from diabetes induction did not prevent reduction in blood flow or sciatic motor conduction velocity. A 37% reduction in endoneurial oxygen tension after 2 months diabetes (p < 0.001) was completely prevented by ZD5522 treatment (p < 0.001). The data show that a very high degree of polyol pathway blockade is necessary to correct nerve functional deficits and that aldose reductase inhibitors have a neurovascular action that does not depend on restoration of nerve myo-inositol.
Asunto(s)
Acetanilidas/farmacología , Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/fisiopatología , Oxígeno/metabolismo , Nervio Ciático/fisiología , Sulfonas/farmacología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Inositol/metabolismo , Masculino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Perfusión , Nervios Periféricos/irrigación sanguínea , Nervios Periféricos/fisiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/irrigación sanguíneaRESUMEN
Increased oxygen free radical activity, coupled with reduced protection against oxidative stress, could play a role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. To test this hypothesis, non-diabetic and streptozotocin-diabetic rats were treated with the anti-oxidant probucol or the pro-oxidant primaquine. One-month diabetes caused 21.4% and 13.6% reduction in sciatic motor and saphenous sensory conduction velocity (p < 0.001). These deficits were prevented by probucol treatment (p < 0.001). After 1-month untreated diabetes, conduction velocity deficits were reversed by a further month of probucol treatment (p < 0.001). For non-diabetic rats, primaquine treatment caused a 12.9% reduction in motor conduction velocity (p < 0.001), which was prevented by probucol treatment (p < 0.001). Primaquine treatment did not affect diabetic rats. Sciatic nerve nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was 48.0% reduced by 2-month diabetes (p < 0.001). This was completely prevented by probucol treatment (p < 0.001). Primaquine treatment did not affect blood flow in diabetic rats. However, in non-diabetic rats it caused a 30.0% reduction (p < 0.01) which was prevented by probucol treatment (p < 0.05). Sciatic endoneurial oxygen tensions were also measured by microelectrode polarography. Mean tension was 38.8% reduced by diabetes (p < 0.001). This was prevented by probucol treatment. Non-diabetic rats given primaquine treatment showed a 21.7% reduction in endoneurial oxygen tension (p < 0.01). The data suggest that vascular-mediated nerve dysfunction in diabetes depends on oxidative stress, and that similar effects in non-diabetic rats may be produced by pro-oxidant treatment. This provides evidence for the potentially important role of oxygen free radical activity in diabetic neuropathy.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Conducción Nerviosa/fisiología , Nervios Periféricos/fisiopatología , Primaquina/farmacología , Probucol/farmacología , Nervio Ciático/fisiopatología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Inositol/metabolismo , Masculino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Conducción Nerviosa/efectos de los fármacos , Oxígeno/análisis , Nervios Periféricos/irrigación sanguínea , Nervios Periféricos/efectos de los fármacos , Polarografía , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Nervio Ciático/efectos de los fármacos , Alcoholes del Azúcar/metabolismoRESUMEN
We examined the effect of the angiotensin II receptor blocker, ZD 8731, on nerve function, capillary density, and blood flow in streptozotocin-diabetic rats. Deficits in sciatic motor and saphenous sensory nerve conduction velocity of 21% and 15%, respectively, were observed after 1 month of diabetes mellitus (p < 0.001). These were completely ameliorated by a further month of ZD 8731 treatment (p < 0.001). Treatment of non-diabetic rats for 1 month with ZD 8731 had no effect on motor or sensory conduction velocity. Sciatic nerve capillary density was not significantly affected by 1- or 2-month untreated diabetes, however, there was a 15% increase in density with ZD 8731 treatment (p < 0.001). Treatment of non-diabetic rats for 1 month had no effect on capillary density. Diabetes prolonged the time taken for 80% conduction failure by 19% (p < 0.05) and 49% (p < 0.001) for 1 and 2 months of diabetes, respectively, when sciatic nerve was exposed to hypoxia in vitro. ZD 8731 treatment during the second month of diabetes limited the prolongation to 22%, not significantly different from 1 month of untreated diabetes but less than for the 2-month diabetic group (p < 0.001). Concentrations of sciatic nerve polyol pathway metabolites were elevated six-fold and myo-inositol was reduced 40% by diabetes; ZD 8731 treatment was without effect. Acute experiments examined the effect of ZD 8731 on sciatic nerve blood flow using laser-Doppler flowmetry. In non-diabetic rats, blood flow changes followed the dose-dependent reductions in systemic arterial pressure and there were no significant variations in sciatic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/farmacología , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Nervios Periféricos/fisiopatología , Quinolinas/farmacología , Nervio Ciático/fisiopatología , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológico , Masculino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Nervios Periféricos/irrigación sanguínea , Nervios Periféricos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/fisiología , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Nervio Ciático/efectos de los fármacosRESUMEN
Essential fatty acid metabolism is impaired by diabetes mellitus and this may be important in the aetiology of peripheral nerve dysfunction. The effects of gamma-linolenic acid (omega-6) and fish oil (omega-3) alone, and in combination, on nerve function and capillarization were examined in 2-month streptozotocin-diabetic rats. Diabetes resulted in approximately 15% and 23% decreases in saphenous sensory and sciatic motor nerve conduction velocities, respectively (p < 0.001). Motor and sensory conduction velocities were in the non-diabetic range after both preventive and reversal omega-6 treatment of diabetic rats (p < 0.001). No significant changes occurred in omega-6 treated non-diabetic rats. Preventive omega-3 treatment was largely ineffective. Reversal treatment with a combination of omega-6 and omega-3 fatty acids was marginally effective and improved motor (p < 0.05), but not sensory conduction velocity. In vitro measurement of sciatic nerve resistance to hypoxic conduction failure in diabetic rats revealed a 56% increase in the time taken for the compound action potential amplitude to be reduced by 80% (p < 0.01) compared to non-diabetic rats. This was partially prevented by omega-6 treatment (29% increase, p < 0.01). Reversal omega-6 treatment had a lesser effect (37% increase, p < 0.05 compared to untreated diabetic rats). omega-3 treatment had no significant effect on conduction failure time. Sciatic endoneurial capillary density increased by 11% with preventive omega-6 treatment (p < 0.05), but was unaffected by reversal omega-6 and by omega-3 treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Capilares/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/farmacología , Nervios Periféricos/fisiopatología , Nervio Ciático/fisiopatología , Ácido gammalinolénico/farmacología , Animales , Capilares/efectos de los fármacos , Hipoxia , Masculino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Conducción Nerviosa/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Nervios Periféricos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Nervio Ciático/irrigación sanguínea , Nervio Ciático/efectos de los fármacos , Factores de TiempoRESUMEN
1. The aims of this study were first, to examine whether deficits in nerve conduction in streptozotocin-diabetic rats could be reversed by a 10% dietary supplement of evening primrose oil. Second, to determine the time-course of reversal, and third, to assess whether the effects could be blocked by the cyclo-oxygenase inhibitor flurbiprofen (5 mg kg-1 day-1). 2. One-month diabetes produced 20% and 15% deficits in sciatic motor and saphenous sensory conduction velocity respectively, which were maintained over 2 months diabetes. 3. The effect of 1-month evening primrose oil treatment on abnormalities caused by an initial month of untreated diabetes was examined. Motor and sensory nerve conduction velocity were restored to the non-diabetic level. 4. Resistance to hypoxic conduction failure was investigated for sciatic nerve trunk in vitro. The 80% conduction failure times were 29% and 55% prolonged by 1- and 2-month diabetes respectively. Evening primrose oil did not reverse the increased hypoxic resistance following 1-month untreated diabetes. 5. Sciatic nerve endoneurial capillary density was not significantly affected by diabetes, but was 16% increased in diabetic rats with reversal by evening primrose oil treatment for 1 month compared to 2-month untreated diabetes. 6. Serial motor conduction velocity measurement after 3-month untreated diabetes revealed complete normalization by evening primrose oil within 4 days. Cessation of treatment resulted in a rapid decline in conduction velocity over 24 h. 7. In a preventive study of 2-month duration, 6 groups of rats were used. These comprised non-diabetic controls, diabetic rats, and evening primrose oil-treated diabetic rats, both with and without flurbiprofen treatment. Flurbiprofen had no significant effect in non-diabetic rats, but produced an 11% worsening of motor conduction velocity and a 21% reduction of sciatic capillary density in diabetic rats. Evening primrose oil prevented the decreases in conduction velocity and increased hypoxic resistance with diabetes, and caused a 23% increase in capillary density. Flurbiprofen completely blocked the effect of evening primrose oil on conduction velocity, resistance to hypoxia, and capillarization.8. Six main conclusions were reached. First, evening primrose oil rapidly reverses conduction deficits in diabetic rats. Second, the effects of treatment may be very short-lived, suggesting a primary metabolic action. Third, evening primrose oil cannot reverse established changes in hypoxic resistance over 1-month treatment. Fourth, long-term treatment causes angiogenesis, suggesting a vascular action. Fifth,products of cyclo-oxygenase-mediated metabolism are necessary for maintaining vasa nervorum integrity in diabetic rats. Sixth, evening primrose oil probably acts by providing substrate for vasodilator prostanoid synthesis by vasa nervorum.