1.Peripheral nerve damage and its pathogenesis induced by antiepileptic drugs in rats.
Min ZHONG ; Fang-cheng CAI ; Xiao-ping ZHANG ; Yan SONG
Chinese Journal of Pediatrics 2008;46(8):574-578
OBJECTIVETo explore the possibility of peripheral nerve damage induced by antiepileptic drugs (AEDs) in different age rats and its pathogenesis.
METHODSAdult (2-month-old) and infant (7-day-old) rats were divided into 8 groups (n = 16 in each) and treated with the following 7 AEDs respectively: phenytoin [PHT, 62.5 mg/(kgxd)], phenobarbital [PB, 30.0 mg/(kgxd)], sodium valproate [VPA, 312.5 mg/(kgxd)], clonazepam [CZP, 1.25 mg /(kgxd)], carbamazepine [CBZ, 187.5 mg/(kgxd)], topiramate [TPM, 40 mg/(kgxd)], oxcarbazepine [OXC, 312.5 mg/(kgxd)], remaining one group was used as control. Four weeks later, 8 rats were sacrificed randomly from each group and serum, sciatic nerves and spinal cord samples were collected. The rest half rats were sacrificed 4 week after AEDs withdrawal. Histological observations were performed on the sciatic nerves samples, including teased fibers, semi-thin sections and electron microscopy. The activity of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in serum and sciatic nerves were detected respectively. Expression of apoptosis-related proteins Bcl-2 and Bax was detected by immunohistochemistry. Neurons apoptosis in the anterior horns of spinal cord were detected by TUNEL.
RESULTS(1) Except for TPM group, various incidence (7.2% - 20.2%) of teased fibers abnormalities were observed in all the other different age groups. PHT group showed the most serious changes followed by PB (adult) or VPA (infant), CBZ, CZP and OXC groups. The predominant abnormality of teased fibers was demyelination. (2) There was no significant difference in the incidence of pathologic changes in teased fibers between adult and infant groups. Four weeks after AEDs withdrawal, recovery of pathologic changes in teased fibers in infant groups was much better than adult. (3) Significantly increased expression of Bax protein and ratio of Bax/Bcl-2 was only found in infant rats treated with PB, CNP or VPA compared with control (P < 0.05), the results of TUNEL was in accordance with immunohistochemistry. (4) Compared with control, the activity of T-AOC and SOD decreased in both infant and adult rats treated with PHT, CZP, CBZ and OXC, and the reduction of SOD activity in serum and sciatic nerves samples was also found in PB groups. Serum activity of GSH-PX was decreased in both age groups treated with PHT, PB, VPA, CZP, CBZ and OXC. The reduction of GSH-PX activity in sciatic nerves samples was remarkably in both adult and infant rats treated with PHT, PB, CBZ, OXC as well as the infant rats treated with CZP.
CONCLUSIONSSix AEDs (PHT, PB, CBZ, VPA, CZP, OXC) showed the potential to cause peripheral nerves damage. Demyelination was the predominant pathologic change. Both adult and infant rats had the same susceptibility. Recovery of pathologic changes in teased fibers in both age groups was slow, but infant rats were prone to revive more quickly. There was no significant correlation between spinal cord neuron apoptosis and peripheral nerves damages in rats treated with AEDs. Breakdown of oxidation-antioxidation balance was closely related to development of peripheral nerves damages caused by most AEDs.
Animals ; Anticonvulsants ; adverse effects ; Demyelinating Diseases ; chemically induced ; pathology ; Oxidative Stress ; Peripheral Nerves ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; pathology ; Spinal Cord ; pathology
2.The role of CYP2E1 in the protection of garlic oil's from n-hexane-induced neurotoxicity.
Ye BI ; Jing-jing CHEN ; Yang LI ; Qiang-qiang FU ; Tao ZENG ; Ke-qin XIE
Chinese Journal of Industrial Hygiene and Occupational Diseases 2011;29(11):825-833
OBJECTIVETo study the role of CYP2E1 in the protective effects and mechanism of garlic oil (GO) on the peripheral nerve injuries induced by n-hexane.
METHODSFifty male Wistar rats were randomly divided into five groups (n = 10): the control, the GO (80 mg/kg) control, the n-hexane (2000 mg/kg) model, the low dose GO (40 mg/kg) plus n-hexane, and the high dose GO (80 mg/kg) plus n-hexane groups. All rats were treated by intragastric administration 6 times a week for 10 weeks. The gait scores were determined every two weeks for monitoring the peripheral neurotrosis. All rats were sacrificed in 10 weeks, the activities and expression levels of hepatic CYP2E1 and 2, 5-HD in serum were examined.
RESULTSAs compared with control group, the content and activity of hepatic CYP2E1 in GO control group reduced by 83.1% and 48.3% respectively (P < 0.01), the content and activity of hepatic CYP2E1 in model group increased by 112.5% and 72.2% respectively (P < 0.01). As compared with model group, the contents of hepatic CYP2E1 in low dose and high dose GO groups reduced by 32.9% and 39.1% respectively, the activities of hepatic CYP2E1 in low dose and high dose GO groups reduced by 27.4% and 44.5% respectively (P < 0.01); the contents of serum 2,5-HD in low dose and high dose GO groups reduced by 47.7% and 78.7% respectively (P < 0.01). The gait scores in model, low dose and high dose GO groups were significantly lower than that in control group, but the gait scores in low dose and high dose GO groups were significantly lower than that in model group (P < 0.05).
CONCLUSIONGarlic oil can effectively reduce the peripheral neurotrosis induced by n-hexane due to the decreased content and activity of hepatic CYP2E1, resulting in the reduced formation of 2, 5-HD from n-hexane.
Animals ; Cytochrome P-450 CYP2E1 ; metabolism ; Garlic ; Hexanes ; toxicity ; Liver ; drug effects ; enzymology ; Male ; Peripheral Nerves ; drug effects ; pathology ; Plant Oils ; pharmacology ; Rats ; Rats, Wistar
3.Effect of Dehydroepiandrosterone on Affected and Unaffected Hindlimb Muscles in Rats with Neuropathic Pain Induced by Unilateral Peripheral Nerve Injury.
Journal of Korean Academy of Nursing 2009;39(5):632-640
PURPOSE: The purpose of this study was to examine the effect of DHEA (Dehydroepiandrosterone) on muscle weight and Type I and II fiber cross-sectional area of affected and unaffected hindlimb muscles in rats with neuropathic pain induced by unilateral peripheral nerve injury. METHODS: Neuropathic pain was induced by ligation and cutting of the left L5 spinal nerve. Adult male Sprague-Dawley rats were randomly assigned to one of two groups: The DHEA group (n=10) had DHEA injections daily for 14 days, and the Vehicle group (n=10) had vehicle injections daily for 14 days. Withdrawal threshold, body weight, food intake and activity were measured every day. At 15 days all rats were anesthetized and soleus, plantaris and gastrocnemius muscles were dissected from the both hindlimbs. Body weight, food intake, activity, muscle weight and Type I, II fiber cross-sectional area of the dissected muscles were measured. RESULTS: The DHEA group showed significant increases (p<.05), as compared to the vehicle group for muscle weight of the unaffected plantaris, and in Type II fiber cross-sectional area of the gastrocnemius muscle. The DHEA group demonstrated a higher pain threshold than the vehicle group whereas total diet intake and activity score were not significantly different between the two groups. CONCLUSION: DHEA administration for 14 days attenuates unaffected plantaris and gastrocnemius muscle atrophy.
Animals
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Body Weight
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Dehydroepiandrosterone/*administration & dosage
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Disease Models, Animal
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Eating/drug effects
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*Hindlimb
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Male
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Muscle Fibers, Skeletal/*drug effects/pathology
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Muscle, Skeletal/drug effects
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Muscular Atrophy/*drug therapy
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Pain/etiology
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Pain Measurement
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Peripheral Nerves/*injuries
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Rats
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Rats, Sprague-Dawley
4.Exploration on the relationship between diabetic peripheral neuropathy and oxidative stress QU ling and.
Chinese Journal of Integrated Traditional and Western Medicine 2007;27(8):764-768
The pathogenesis of diabetic peripheral neuropathy (DPN) is not illustrated clearly nowadays, and there are several hypotheses. Oxidative stress response is penetrated in several different hypotheses as the formation of advanced glycosylation end products, polyhydric alcohol metabolic pathway, protein kinase C activation and microvascular lesion, etc. The influence of oxidative stress on DPN and the current status of anti-oxidation therapy by using integrative traditional and Western medicine were reviewed in this paper.
Antioxidants
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therapeutic use
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Diabetic Neuropathies
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drug therapy
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physiopathology
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Drug Therapy, Combination
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Drugs, Chinese Herbal
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therapeutic use
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Humans
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Oxidative Stress
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drug effects
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physiology
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Peripheral Nerves
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drug effects
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pathology
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physiopathology
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Phytotherapy
5.Damage to peripheral nerves induced by Campylobacter jejuni exotoxin.
Long-shan XIE ; Fang-cheng CAI ; Yu-xing GAO ; Xiao-ping ZHANG
Chinese Journal of Pediatrics 2003;41(12):934-939
OBJECTIVETo explore the pathogenesis of the damage to peripheral nerves induced by Campylobacter jejuni exotoxin (CJT).
METHODS(1) Animal models: (1) The CJT was extracted from PEN 19-CJ and injected perineurally and intravenously to Wistar rats. (2) The sera and the supernatants of peripheral blood mononuclear cells (PBMCs), taken from the rats immunized with the CJT, were injected perineurally at sciatic nerves of experimental rats and intravenously, respectively. (2) Histopathologic study of sciatic nerves: the animals were sacrificed and their sciatic nerves were examined for tease fibers, transverse section with toluidine blues staining and electron microscopy. (3) Immunohistochemistry: sections of sciatic nerves of either normal rats or human which were incubated with CJT and the sciatic nerves with pathological changes induced by CJT were obtained for observation of the binding capability of CJT with peripheral nerves by SABC and FITC-immunofluorescence methods, and nucleic acid hybridization techniques for detection of TNF-alpha mRNA expression in pathological sciatic nerves samples.
RESULTS(1) Remarkable peripheral neuropathies with axon degeneration and/or demyelination were found in the nerves induced by both CJT injection perineurally and intravenously. The axon degeneration was more obvious. Pathological changes were identified in 76.8% (2,763/3,600) of teasing fibers after perineural injection, but only 9.6% (230/2,400) of fibers were damaged in control group (P < 0.01). The peak severity of fiber damage was found on the 3rd day after CJT intravenous injection with the incidence of abnormal fibers was 19.5% (390/2,000), and abnormalities of 15.5% (310/2000) on the 14th day. However, no abnormal changes were demonstrated in control group (P < 0.01). So was in the groups injected with anti-CJT sera and the supernatants of PBMCs compared with control (P > 0.05). (2) Binding of CJT to the nerve was found dominant in the sciatic nerves taken from normal rats or human either incubated with CJT or in the pathological sciatic nerves induced by CJT to various degrees. The binding of CJT to all these nerves was determined. (3) After intravenous injection with CJT, no histopathologic change could be found in the other viscera of the rats, with the exception of remarkable pathological change in peripheral nerves.
CONCLUSIONS(1) CJT could remarkably damage the peripheral nerves in rats. Specific pathogenicity of CJT to peripheral nerves was well shown, because no histopathologic abnormalities could be found in the other viscera, such as brain, liver and kidney etc. although there was remarkable pathological change along the peripheral nerve in the animals. (2) No immunological pathogenicity of CJT could be demonstrated in the nerves of rats after immunization with CJT.
Animals ; Antibodies, Anti-Idiotypic ; blood ; Bacterial Toxins ; immunology ; toxicity ; Campylobacter jejuni ; immunology ; Exotoxins ; immunology ; toxicity ; Gene Expression ; drug effects ; Peripheral Nerves ; drug effects ; metabolism ; pathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Sciatic Nerve ; drug effects ; metabolism ; pathology ; Tumor Necrosis Factor-alpha ; genetics
6.Neuroprotective effects of Vitis vinifera extract on prediabetic mice induced by a high-fat diet.
Heung Yong JIN ; Youn Soo CHA ; Hong Sun BAEK ; Tae Sun PARK
The Korean Journal of Internal Medicine 2013;28(5):579-586
BACKGROUND/AIMS: Vitis vinifera grape seed extract (VVE) contains oligomeric proanthocyanidins that show antioxidant and free radical-scavenging activities. We evaluated VVE for its neuroprotective effect in prediabetic mice induce by a high-fat diet (HD). METHODS: Mice were divided into four groups according to VVE dose: those fed a normal diet (ND; n = 10), HD (n = 10), HD with 100 mg/kg VVE (n = 10), and HD with 250 mg/kg VVE (n = 10). After 12 weeks, immunohistochemical analyses were carried out using a polyclonal antibody against antiprotein gene product 9.5 (protein-gene-product, 9.5), and intraepidermal innervation was subsequently quantified as nerve fiber abundance per unit length of epidermis (intraepidermal nerve fiber, IENF/mm). RESULTS: Daily administration of VVE at doses of 100 or 250 mg/kg for 12 weeks protected HD mice from nerve fiber loss compared to untreated mice, as follows (IENF/mm): controls (40.95 +/- 5.40), HD (28.70 +/- 6.37), HD with 100 mg/kg (41.14 +/- 1.12), and HD with 250 mg/kg (48.98 +/- 7.01; p < 0.05, HD with VVE vs. HD). CONCLUSIONS: This study provides scientific support for the therapeutic potential of VVE in peripheral neuropathy in an HD mouse model. Our results suggest that VVE could play a role in the management of peripheral neuropathy, similar to other antioxidants known to be beneficial for diabetic peripheral neuropathy.
Animals
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Antioxidants/*pharmacology
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Biological Markers/blood
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Blood Glucose/drug effects/metabolism
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Body Weight/drug effects
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Diabetic Neuropathies/blood/etiology/pathology/*prevention & control
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*Diet, High-Fat
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Epidermis/*innervation
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Grape Seed Extract/*pharmacology
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Lipids/blood
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Male
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Mice
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Mice, Inbred C57BL
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Neuroprotective Agents/*pharmacology
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Peripheral Nerves/*drug effects/pathology
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Phytotherapy
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Plants, Medicinal
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Prediabetic State/blood/*drug therapy/etiology
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Time Factors
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*Vitis