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1.
Muscle Nerve ; 24(12): 1601-6, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11745968

RESUMEN

The immunosuppressant agent FK506 (tacrolimus) has proven to be neuroprotective against brain ischemia, but there are no data on potential neuroprotective effects of FK506 in peripheral nerve ischemia. We examined the potential effects of two doses of FK506 in protecting peripheral nerve from ischemic fiber degeneration. Ischemia in the left sciatic nerve of the rat was produced by injecting 2 x 10(6) microspheres (14 microm) into the left femoral, hypogastric, and superior gluteal arteries in proportions of 47%, 37%, and 17%, respectively. After embolization, FK506 was injected into the left femoral, hypogastric, and superior gluteal arteries in doses of 9.4, 7.4, and 3.4 microg, respectively, for the high-dose group and 4.7, 3.7, and 1.7 microg, respectively, for the low-dose group. The control rats were injected with saline. FK506 treatment resulted in dramatic behavioral improvement in nerve function, in the number of functioning nerve fibers, and in the salvage of a majority of nerve fibers from ischemic fiber degeneration in a dose-dependent fashion. These results suggest that a small dose of FK506 protects peripheral nerve from ischemic fiber degeneration and that it may have potential in the treatment of ischemic neuropathy.


Asunto(s)
Inmunosupresores/farmacología , Isquemia/tratamiento farmacológico , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/prevención & control , Tacrolimus/farmacología , Nervio Tibial/patología , Potenciales de Acción , Animales , Conducta Animal , Relación Dosis-Respuesta a Droga , Electrofisiología , Isquemia/patología , Masculino , Degeneración Nerviosa/patología , Fibras Nerviosas/patología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional
2.
Exp Neurol ; 169(2): 386-91, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11358451

RESUMEN

Cytokines may be pathophysiologically involved in hyperalgesia. Uncertainty exists about the types of cytokines and their site of action. To study the role of key pro- and anti-inflammatory cytokines in a chronic constriction model of neuropathic pain, mRNA expression of TNF, IL-1beta, IL-6, and IL-10 was quantified using competitive RT-PCR. Each cytokine mRNA in rat sciatic nerve was examined at days 3, 7, 14, and 45 after chronic constriction injury (CCI). We also undertook behavioral testing of these rats. Thermal warming and touch thresholds were significantly reduced at days 3, 7, and 14 in the CCI group, compared with the sham-operated group. Cytokine gene expression in sciatic nerve was significantly increased at day 7 for IL-1beta and IL-6 and at day 14 for TNF. Expression of IL-10 underwent a gradual and progressive increase, reaching statistical significance at day 45.


Asunto(s)
Citocinas/genética , Regulación de la Expresión Génica/fisiología , Neuralgia/fisiopatología , Nervio Ciático/fisiopatología , Transcripción Genética , Animales , Constricción , Inflamación , Interleucina-1/genética , Interleucina-10/genética , Interleucina-6/genética , Masculino , Neuralgia/inmunología , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nervio Ciático/inmunología , Ciática/inmunología , Ciática/fisiopatología , Factores de Tiempo , Tacto , Factor de Necrosis Tumoral alfa/genética
3.
J Peripher Nerv Syst ; 5(1): 11-8, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10780678

RESUMEN

Chronic hyperglycemia results in a large deficit in nerve blood flow. Both autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant peripheral sensory neuropathy in streptozotocin-induced diabetes in the rat. Free radical defenses, especially involving antioxidant enzymes, have been suggested to be reduced, but scant information is available on chronic hyperglycemia. We evaluated the gene expression of glutathione peroxidase, catalase, and superoxide dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG) and superior cervical ganglion, as well as enzyme activity of glutathione peroxidase in DRG and sciatic nerve in experimental diabetic neuropathy of 3 months and 12 months durations. We also evaluated nerve electrophysiology of caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen in all nerves in experimental diabetic neuropathy at both 3 and 12 months. Gene expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase, and manganese superoxide dismutase were not reduced in experimental diabetic neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in experimental diabetic neuropathy at 12 months. Glutathione peroxidase enzyme activity was normal in sciatic nerve. We conclude that gene expression is not reduced in peripheral nerve tissues in very chronic experimental diabetic neuropathy. Changes in enzyme activity may be related to duration of diabetes or due to post-translational modifications.


Asunto(s)
Neuropatías Diabéticas/enzimología , Regulación Enzimológica de la Expresión Génica , Superóxido Dismutasa/genética , Animales , Glucemia , Northern Blotting , Peso Corporal , Catalasa/genética , Catalasa/metabolismo , Clonación Molecular , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/genética , Neuropatías Diabéticas/genética , Electrofisiología , Ganglios Espinales/enzimología , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Hemoglobina Glucada/análisis , Masculino , Conducción Nerviosa/fisiología , Estrés Oxidativo/fisiología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Nervio Ciático/enzimología , Ganglio Cervical Superior/enzimología , Superóxido Dismutasa/metabolismo
4.
Mech Ageing Dev ; 114(1): 5-14, 2000 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-10731577

RESUMEN

This study examined the influence of the vaso-constricting agents (noradrenaline, endothelin-1 and angiotensin II) in Sprague-Dawley rats aged 2, 6 and 24 months by evaluating epineurial arteriolar vasoreactivity in response to superfused teat agents. Nerve blood flow (NBF) was measured using microelectrode H2 polarography. In 24-month-old rats, NBF was decreased and vascular resistance (VR) was increased compared with 2- and 6-month-old rats. All of the constricting agents reduced NBF in the 2-, 6- and 24-month groups, however, the effects of the constricting agents reduced significantly with age. These results suggest that during aging, there is a decline of vasoconstrictive responses to noradrenaline, endothelin-1 and angiotensin II in peripheral nerve and that these changes may be due to altered function of receptors.


Asunto(s)
Envejecimiento/fisiología , Angiotensina II/farmacología , Arteriolas/efectos de los fármacos , Endotelina-1/farmacología , Norepinefrina/farmacología , Nervio Ciático/irrigación sanguínea , Vasoconstrictores/farmacología , Animales , Arteriolas/fisiología , Presión Sanguínea , Ratas , Ratas Sprague-Dawley
5.
Brain ; 123 Pt 3: 519-31, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10686175

RESUMEN

Recent pathological studies have re-emphasized that axonal injury is present in patients with multiple sclerosis, the most common demyelinating disease of the CNS in humans. However, the temporal profile of demyelination and axonal loss in multiple sclerosis patients and their independent contributions to clinical and electrophysiological abnormalities are not completely understood. In this study, we used the Theiler's murine encephalomyelitis virus model of progressive CNS inflammatory demyelination to demonstrate that demyelination in the spinal cord is followed by a loss of medium to large myelinated fibres. By measuring spinal cord areas, motor-evoked potentials, and motor coordination and balance, we determined that axonal loss following demyelination was associated with electrophysiological abnormalities and correlated strongly with reduced motor coordination and spinal cord atrophy. These findings demonstrate that axonal loss can follow primary, immune-mediated demyelination in the CNS and that the severity of axonal loss correlates almost perfectly with the degree of spinal cord atrophy and neurological deficits.


Asunto(s)
Axones/patología , Esclerosis Múltiple/patología , Poliomielitis/patología , Enfermedades de la Médula Espinal/patología , Theilovirus , Animales , Atrofia , Modelos Animales de Enfermedad , Potenciales Evocados Motores , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/virología , Fibras Nerviosas Mielínicas/inmunología , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Mielínicas/virología , Conducción Nerviosa , Examen Neurológico , Poliomielitis/inmunología , Desempeño Psicomotor , Médula Espinal/patología , Enfermedades de la Médula Espinal/inmunología , Enfermedades de la Médula Espinal/virología
6.
Diabetes ; 48(10): 2045-51, 1999 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10512372

RESUMEN

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metabolism, requiring increased energy substrate stores. When glucose stores become reduced, fiber degeneration has been reported. We evaluated glucose uptake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC) activity in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 month, and alpha-lipoic acid was administered intraperitoneally 5 times per week for the final week of the experiment. Nerve glucose uptake was reduced to 60, s 37, and 30% of control values in the sciatic nerve, L5 dorsal root ganglion, and superior cervical ganglion (SCG), respectively, in rats with EDN. Alpha-lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in EDN, with a threshold between 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and myo-inositol were measured in sciatic nerve. Alpha-lipoic acid had no significant effect on either energy metabolism or polyol pathway of normal nerves. In EDN, endoneurial glucose, fructose, and sorbitol were significantly increased, while myo-inositol was significantly reduced. Alpha-lipoic acid had a biphasic effect: it dose-dependently increased fructose, glucose, and sorbitol, peaking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased myo-inositol. Sciatic nerve cytosolic PKC was increased in EDN. ATP, creatine phosphate, and lactate were measured in sciatic nerve and SCG. Alpha-lipoic acid prevented the reduction in SCG creatine phosphate. We conclude that glucose uptake is reduced in EDN and that this deficit is dose-dependently reversed by alpha-lipoic acid, a change associated with an improvement in peripheral nerve function.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Sorbitol/metabolismo , Ácido Tióctico/farmacología , Animales , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Fructosa/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Inositol/metabolismo , Masculino , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Ácido Tióctico/metabolismo
7.
Brain Res ; 844(1-2): 192-5, 1999 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-10536276

RESUMEN

We evaluated the proinflammatory cytokines, TNF-alpha and IL-1beta, mRNA expression in the rat sciatic and tibial nerves following ischemia-reperfusion (IR) injury, using competitive RT-PCR, to explore the role of cytokines in IR injury. The expressions of both TNF-alpha and IL-1beta mRNA were related to severity of ischemia and occurred with reperfusion rather than ischemia alone. TNF-alpha gene expression peaked at 24 h of reperfusion, while that of IL-1beta peaked at 12 h. These data support the notion that the proinflammatory cytokines TNF-alpha and IL-1beta are involved in the inflammatory response of IR injury to the peripheral nervous system and may be involved in the pathophysiology of ischemic fiber degeneration.


Asunto(s)
Interleucina-1/genética , Daño por Reperfusión/fisiopatología , Nervio Tibial/irrigación sanguínea , Nervio Tibial/fisiología , Factor de Necrosis Tumoral alfa/genética , Animales , ADN Complementario , Expresión Génica/fisiología , Masculino , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley
8.
Muscle Nerve ; 22(7): 920-5, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10398211

RESUMEN

We evaluated the effects of angiotensin II and an angiotensin-converting enzyme inhibitor (cilazapril) on nerve blood flow (NBF) and electrophysiology in control and diabetic rats. When applied locally to the sciatic nerve, the dose-response curve of angiotensin II was more potent in experimental diabetic neuropathy (EDN) than control rats. No difference existed in plasma angiotensin II levels between EDN and controls. The rats were given typical rat pellets or pellets treated with 10 mg/kg per day cilazapril for 4 weeks. Diabetes caused a significant reduction in NBF, nerve conduction velocity, and compound muscle action potential (CMAP) amplitudes. NBF was significantly increased in diabetic rats supplemented with cilazapril diet, and nerve conduction velocity and amplitudes of the CMAP were also improved after 4 weeks on this diet. Direct application 10(-3) mol/L cilazapril on sciatic nerve did not increase NBF in normal and EDN rats. We topically applied the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine, on sciatic nerve and observed reduced inhibition of NBF in EDN, which was correctable with a cilazapril diet. These results suggest that diabetic neuropathy may have an increasing vasopressor action with angiotensin II and this is likely to be the mechanism of NOS inhibition. Angiotensin II-converting enzyme inhibitors may have potential in the treatment of diabetic neuropathy.


Asunto(s)
Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cilazapril/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Óxido Nítrico/fisiología , Sistema Vasomotor/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/fisiopatología , Relación Dosis-Respuesta a Droga , Modelos Logísticos , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos
9.
Brain Res ; 827(1-2): 63-9, 1999 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-10320694

RESUMEN

The pathophysiology of ischemic fiber degeneration (IFD) is not known, but mechanisms involved during nerve ischemia differ from those during reperfusion. We have previously demonstrated hypothermic neuroprotection of peripheral nerve from IFD. We now evaluate the efficacy of hypothermia in the intraischemic vs. the reperfusion period, using our established model of ischemia-reperfusion injury. Intraischemic hypothermia resulted in significant recovery of all indices (behavior score, electrophysiology and histology, P<0.01 or 0.05) while hypothermia during reperfusion period showed less improvement, significant only for the histological score compared to normothermia group (IFD index, P<0.05). Once hypothermia was applied in the ischemic period, the resultant neuroprotection continued into the reperfusion period, even if nerve temperature was then raised during the reperfusion period. These results indicate that hypothermic neuroprotection is more efficacious during the intraischemic period than during reperfusion, when a lesser degree of neuroprotection ensued.


Asunto(s)
Hipotermia Inducida , Daño por Reperfusión/terapia , Nervio Tibial/irrigación sanguínea , Potenciales de Acción/fisiología , Animales , Conducta Animal/fisiología , Electrofisiología , Ligadura , Masculino , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Fibras Nerviosas/patología , Ratas , Ratas Sprague-Dawley , Nervio Tibial/patología , Factores de Tiempo
10.
J Neurol Sci ; 163(1): 11-6, 1999 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-10223404

RESUMEN

BACKGROUND: Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic alpha-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. METHODS: We used male SD rats, 300+/-5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously. RESULTS: Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia). CONCLUSION: These results suggest that alpha-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.


Asunto(s)
Isquemia/fisiopatología , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/prevención & control , Nervio Ciático/irrigación sanguínea , Ácido Tióctico/farmacología , Nervio Tibial/irrigación sanguínea , Potenciales de Acción , Animales , Marcha , Miembro Posterior/irrigación sanguínea , Isquemia/patología , Masculino , Músculo Esquelético/inervación , Fármacos Neuroprotectores/uso terapéutico , Dolor , Postura , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/patología , Nervio Ciático/patología , Nervio Ciático/fisiopatología , Ácido Tióctico/uso terapéutico , Nervio Tibial/patología , Nervio Tibial/fisiopatología
11.
Brain ; 122 ( Pt 1): 161-9, 1999 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10050903

RESUMEN

Although there is much information on experimental ischaemic neuropathy, there are only scant data on neuroprotection. We evaluated the effectiveness of hypothermia in protecting peripheral nerve from ischaemia-reperfusion injury using the model of experimental nerve ischaemia. Forty-eight male Sprague-Dawley rats were divided into six groups. We used a ligation-reperfusion model of nerve ischaemia where each of the supplying arteries to the sciatic-tibial nerves of the right hind limb was ligated and the ligatures were released after a predetermined period of ischaemia. The right hind limbs of one group (24 rats) were made ischaemic for 5 h and those of the other group (24 rats) for 3 h. Each group was further divided into three and the limbs were maintained at 37 degrees C (36 degrees C for 5 h of ischaemia) in one, 32 degrees C in the second and 28 degrees C in the third of these groups for the final 2 h of the ischaemic period and an additional 2 h of the reperfusion period. A behavioural score was recorded and nerve electrophysiology of motor and sensory nerves was undertaken 1 week after surgical procedures. At that time, entire sciatic-tibial nerves were harvested and fixed in situ. Four portions of each nerve were examined: proximal sciatic nerve, distal sciatic nerve, mid-tibial nerve and distal tibial nerve. To determine the degree of fibre degeneration, each section was studied by light microscopy, and we estimated an oedema index and a fibre degeneration index. The groups treated at 36-37 degrees C underwent marked fibre degeneration, associated with a reduction in action potential and impairment in behavioural score. The groups treated at 28 degrees C (for both 3 and 5 h) showed significantly less (P < 0.01; ANOVA, Bonferoni post hoc test) reperfusion injury for all indices (behavioural score, electrophysiology and neuropathology), and the groups treated at 32 degrees C had scores intermediate between the groups treated at 36-37 degrees C and 28 degrees C. Our results showed that cooling the limbs dramatically protects the peripheral nerve from ischaemia-reperfusion injury.


Asunto(s)
Hipotermia Inducida , Isquemia/prevención & control , Daño por Reperfusión/prevención & control , Nervio Ciático/irrigación sanguínea , Nervio Tibial/irrigación sanguínea , Potenciales de Acción/fisiología , Animales , Conducta Animal/fisiología , Ligadura , Masculino , Músculo Esquelético/fisiopatología , Degeneración Nerviosa/patología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/patología , Nervio Tibial/patología
12.
Brain ; 120 ( Pt 3): 445-9, 1997 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9126056

RESUMEN

We studied blood flow rates along the sciatic nerve and in the superior cervical and L-5 dorsal root ganglia of rats at rest and during reductions and increases in mean arterial pressure induced by partial exsanguination or blood transfusion. Blood flow was measured by the tissue distribution of [14C]iodoantipyrine and autoradiography. At rest, blood flow did not vary along the peripheral nerve, but was two to three times greater in dorsal root and superior cervical ganglia. In peripheral nerve, blood flow increased with increases in blood pressure. In contrast, blood flow in dorsal root and sympathetic ganglia did not vary with changes in pressure. Thus, peripheral nerve cell bodies have greater blood flow than their axons; ganglion blood flow is autoregulated within the range of blood pressure tested. Nerve ganglia appear to be protected against ischaemic stress by autoregulation rather than by a blood flow "safety margin', as in peripheral nerve.


Asunto(s)
Velocidad del Flujo Sanguíneo , Ganglios Simpáticos/irrigación sanguínea , Ganglios Simpáticos/fisiología , Nervio Ciático/irrigación sanguínea , Nervio Ciático/fisiología , Animales , Presión Sanguínea , Ganglios Espinales/irrigación sanguínea , Ganglios Espinales/fisiología , Homeostasis , Masculino , Ratas , Ratas Sprague-Dawley
13.
Acta Neuropathol ; 93(2): 118-28, 1997 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9039458

RESUMEN

Vascular perfusion and neuropathologic evaluation of the lumbar spinal roots and dorsal root ganglia (DRG) were studied in rats with longstanding (duration 12-15 months) streptozotocin-induced diabetes and age- and sex-matched control rats. We also undertook nerve conduction studies including F-wave recordings and measured blood flow in sciatic nerve, DRG, and superior cervical ganglion (SCG). Light microscopically, changes of the myelin sheath in the dorsal and ventral roots and vacuolated cells in the DRG were the major findings, being significantly higher in diabetic rats than in control rats. The effects of the diabetic state on myelin splitting were greater in the dorsal than ventral roots. Electron microscopic studies revealed a gradation of changes in myelin from mild separation to severe ballooning of myelin with relative axonal sparing. DRG cells showed vacuoles of all sizes with cristae-like residues, suggestive of mitochondria. These findings suggest that diabetes mellitus has a dual effect: it accelerates the normal age-related degenerative changes in the spinal roots and DRG, and it also has a selective effect on the sensory neuron. Nerve conduction studies showed markedly reduced conduction velocities in the distal nerve segments and prolonged F-wave latency and proximal conduction time despite the shorter conduction pathway in diabetic rats. Blood flow, which was measured using iodo[14C]antipyrine autoradiography, was significantly reduced in the sciatic nerves, DRG, and SCG of diabetic rats. We suggest that the combination of hyperglycemia and ischemia results in oxidative-stress and a predominantly sensory neuropathy.


Asunto(s)
Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Ganglios Espinales/patología , Nervio Ciático/patología , Raíces Nerviosas Espinales/patología , Nervio Tibial/patología , Animales , Electrofisiología , Ganglios Espinales/irrigación sanguínea , Ganglios Espinales/ultraestructura , Masculino , Ratas , Ratas Sprague-Dawley , Nervio Ciático/irrigación sanguínea , Nervio Ciático/ultraestructura , Raíces Nerviosas Espinales/irrigación sanguínea , Raíces Nerviosas Espinales/ultraestructura , Ganglio Cervical Superior/irrigación sanguínea , Ganglio Cervical Superior/patología , Ganglio Cervical Superior/ultraestructura , Nervio Tibial/irrigación sanguínea , Nervio Tibial/ultraestructura
14.
Acta Neuropathol ; 93(1): 62-70, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9006658

RESUMEN

We evaluated the nerve blood flow (NBF), light and electron microscopy, and adrenergic innervation of rat sciatic nerve at 2-45 days after the application of four loose ligatures. Ischemia developed at the lesion edge, creating an endoneurial dam. Calcitonin gene-related peptide, norepinephrine and NBF were increased within the lesion. Morphologic alterations consisted of early endoneurial edema, followed by myelinated fiber degeneration, with relative sparing of small myelinated and unmyelinated nerve fibers, and leukocyte adhesion to microvessels. Axonal degeneration predominated over demyelination. At 45 days, profuse regeneration of small myelinated fibers was seen. The mechanism of lesional sensitization is discussed.


Asunto(s)
Enfermedades del Sistema Nervioso Periférico/patología , Nervio Ciático/irrigación sanguínea , Nervio Ciático/patología , Animales , Enfermedad Crónica , Constricción Patológica , Masculino , Modelos Biológicos , Norepinefrina/metabolismo , Enfermedades del Sistema Nervioso Periférico/etiología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Nervio Ciático/ultraestructura
15.
Muscle Nerve ; 19(2): 203-9, 1996 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8559170

RESUMEN

Since peripheral nerve has a large ischemic safety factor, hypothermia, by reducing metabolic demands, is potentially an efficacious technique to rescue nerve from ischemic fiber degeneration (IFD). We therefore evaluated the influence of temperature on the severity of IFD resulting from a standard ischemic stress. Ischemia to the left sciatic nerve in the rat was produced by embolization of 2 x 10(6) microspheres (14 microns) into its supplying arteries. The limb was embolized at three temperatures, 37 degrees C, 32 degrees C, and 28 degrees C and was maintained at each temperature for an additional 4 h. End points, evaluated 7 days after embolization, for the embolized limb were: (1) behavioral scores, 0-11 in increasing limb function; (2) compound nerve action potential of sciatic-tibial nerve; (3) sciatic nerve blood flow (NBF, in mL/100 g/min); and (4) histologic grade, expressed as percentage of fibers undergoing IFD (0 = < 5%; 1 = 5-25%; 2 = 26-50%; 3 = 51-75%; 4 = > 75%). NBF was reduced in all groups, varying with temperature, and all indices of nerve structure and function were significantly improved with hypothermia. We conclude that hypothermia, easily achievable in a limb nerve, is highly efficacious in the rescue of nerve from IFD. These findings are of clinical relevance.


Asunto(s)
Hipotermia/fisiopatología , Isquemia/fisiopatología , Degeneración Nerviosa/fisiología , Sistema Nervioso Periférico/fisiología , Animales , Temperatura Corporal/fisiología , Masculino , Conducción Nerviosa/fisiología , Ratas , Ratas Sprague-Dawley
16.
Muscle Nerve ; 19(1): 37-47, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8538668

RESUMEN

Although the neuropathology of ischemic fiber degeneration (IFD) is relatively well known, its pathogenesis is poorly understood. One putative mechanism of IFD is oxidative stress, causing a breakdown of the blood-nerve barrier (BNB) and lipid peroxidation. We evaluated the effect of ischemic reperfusion of rat sciatic-tibial nerve seeking biochemical and pathologic evidence of BNB disruption and lipid peroxidation. Ischemia, caused by the ligation of the supplying arteries to sciatic-tibial nerve, was maintained for 3 h, followed by reperfusion. Reperfusion resulted in an increase in nerve lipid hydroperoxides, greatest at 3 h, followed by a gradual decline over the next month. Nerve edema and IFD consistently became more severe with reperfusion, indicating that oxidative stress impairs the BNB (edema) and causes IFD. Reduced reperfusion was greatest over distal sciatic nerve and midtibial nerve at day 7. The most ischemic segment (midtibial), of nonreperfused ischemic nerves (duration 3 h), underwent both edema and IFD that was as pronounced as those of other segments after reperfusion, and underwent a smaller increase with reperfusion, suggesting that ischemia alone can also cause IFD and edema. The type of fiber degeneration was that of axonal degeneration.


Asunto(s)
Peróxidos Lipídicos/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Nervio Ciático/irrigación sanguínea , Nervio Tibial/irrigación sanguínea , Animales , Masculino , Fibras Nerviosas/patología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/fisiopatología , Nervio Ciático/patología , Nervio Ciático/fisiopatología , Nervio Tibial/patología , Nervio Tibial/fisiopatología
17.
Diabetologia ; 38(8): 914-8, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7589876

RESUMEN

Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC50 of 10(-5.74) mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10(-4) mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/fisiopatología , Inhibidores de Fosfodiesterasa/farmacología , Tetrazoles/farmacología , Vasodilatadores/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cilostazol , Diabetes Mellitus Experimental/sangre , Neuropatías Diabéticas/sangre , Alimentos Fortificados , Masculino , Conducción Nerviosa/efectos de los fármacos , Nervios Periféricos/irrigación sanguínea , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiopatología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiopatología , Tetrazoles/administración & dosificación , Tetrazoles/uso terapéutico , Nervio Tibial/efectos de los fármacos , Nervio Tibial/fisiopatología , Vasodilatadores/administración & dosificación , Vasodilatadores/uso terapéutico
18.
Diabetes Care ; 18(8): 1160-7, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7587852

RESUMEN

OBJECTIVE: To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS: We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS: NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS: These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Conducción Nerviosa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Nervio Ciático/fisiopatología , Ácido Tióctico/farmacología , Animales , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Ganglios Espinales/metabolismo , Glutatión/metabolismo , Humanos , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Factores de Tiempo , Deficiencia de Vitamina A/fisiopatología , Vitamina E/metabolismo , Pérdida de Peso
19.
Ann Neurol ; 37(1): 89-94, 1995 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-7818263

RESUMEN

Hyperbaric oxygenation is effective in augmenting the delivery of oxygen to tissue, but also causes oxidative stress. As part of our focus on improving peripheral nerve salvage from ischemic fiber degeneration, we evaluated whether hyperbaric oxygenation rescues peripheral nerve, rendered ischemic by microembolization, from ischemic fiber degeneration. The supplying arteries of rat sciatic nerve were embolized with microspheres of 14 microns diameter at moderate (2 x 10(6)) and high (5.6 x 10(6)) doses. Rats were randomized to receive hyperbaric oxygenation treatment (2.5 atm 100% oxygen for 2 hours/day for 7 days beginning within 30 minutes of ischemia), or room air. End points for the embolized limb were (1) behavioral scores (0-11 in increasing levels of limb function), (2) nerve action potential of sciatic-tibial nerve, (3) nerve blood flow, and (4) histological grade as percentage of fibers undergoing ischemic fiber degeneration (0 = < 5%; 1 = 5-25%; 2 = 26-50%; 3 = 51-75%; 4 = > 76%). Nerve blood flow and nerve action potential were uniformly absent and more than 90% of fibers had degenerated in both control and treatment groups receiving high doses. Control and treatment groups receiving moderate doses were well matched by level of ischemia (8.5 +/- 0.3 [N = 18] vs 7.7 +/- 0.4 ml/100 gm/min [N = 18], p > 0.05) but were significantly different by behavior score (5.6 +/- 0.7 vs 9.2 +/- 0.5 [N = 19], p < 0.001), nerve action potential (1.4 +/- 1.0 vs 3.9 +/- 0.5 [N = 6], p < 0.05), and histology (2.4 +/- 0.4 [N = 5] vs 0.8 +/- 0.5 [N = 4], p < 0.05). On single teased fiber evaluation, the predominant abnormality was E (axonal degeneration). We conclude that hyperbaric oxygenation will effectively rescue fibers from ischemic fiber degeneration, providing the ischemia is not extreme.


Asunto(s)
Oxigenoterapia Hiperbárica , Isquemia/terapia , Nervios Periféricos/irrigación sanguínea , Enfermedades del Sistema Nervioso Periférico/terapia , Potenciales de Acción/fisiología , Animales , Edema/patología , Humanos , Isquemia/patología , Isquemia/fisiopatología , Masculino , Conducción Nerviosa/fisiología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Nervio Ciático/irrigación sanguínea , Nervio Ciático/patología , Nervio Ciático/fisiología
20.
J Neurol Sci ; 126(1): 6-14, 1994 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7836948

RESUMEN

We tested the hypothesis that oxidative stress can cause neuropathy by evaluating the effect of alpha-tocopherol depletion in normal and streptozotocin (STZ) diabetic peripheral nerve (known to be subject to oxidative stress). The end points were nerve electrophysiology and indices of oxidative stress. Studies were done on 6 groups of rats at 1 and 3 months: (1) Controls, normal alpha-tocopherol (Con[N]). (2) Controls, alpha-tocopherol-deficient (Con[-]) (3) Controls, alpha-tocopherol supplemented (Con[+]); (4) Diabetic, normal alpha-tocopherol (STZ[N]); (5) Diabetic, alpha-tocopherol-deficient (STZ[-]) (6) Diabetic, alpha-tocopherol supplemented (STZ[+]). An alpha-tocopherol-deficient diet resulted in a rapid depletion of the vitamin in plasma and sympathetic neurones (superior cervical ganglion), and a slower depletion in sensory neurones (dorsal root ganglion) and nerve. The depletion was associated with a reduction in reduced glutathione and an increase in conjugated dienes and hydroperoxides in normal rats, and resulted in similar changes, or accentuated the abnormalities, in diabetic nerves. Changes were more pronounced at 1 than 3 months and alpha-tocopherol supplementation, for the most part, did not prevent the abnormalities. alpha-Tocopherol depletion induced or worsened nerve conduction abnormalities in both sciatic-tibial and caudal nerves. Sensory fibers were more affected than motor fibers and the changes were more pronounced at 3 than 1 month. These findings support the notion that oxidative stress may cause neuropathy and that it might be mechanistically implicated in experimental diabetic neuropathy (STZ-EDN).


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/metabolismo , Estrés Oxidativo , Nervios Periféricos/metabolismo , Deficiencia de Vitamina E/complicaciones , Vitamina E/fisiología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Neuropatías Diabéticas/complicaciones , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Glutatión/análisis , Peróxido de Hidrógeno/análisis , Peroxidación de Lípido/efectos de los fármacos , Microcirculación , Conducción Nerviosa/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Norepinefrina/análisis , Ratas , Estreptozocina , Ganglio Cervical Superior/metabolismo , Ganglio Cervical Superior/patología , Vitamina E/administración & dosificación , Vitamina E/uso terapéutico , Deficiencia de Vitamina E/tratamiento farmacológico
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