Neuroprotective Effect of Curcumin on the Nigrostriatal Pathway in a 6-Hydroxydopmine-Induced Rat Model of Parkinson's Disease is Mediated by α7-Nicotinic Receptors.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic nigrostriatal neurons. Most of the existing pharmacological approaches in PD consider replenishing striatal dopamine. It has been reported that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptor (α7-nAChR) stimulation may offer a potential therapeutic approach in PD. Our recent in-vitro studies demonstrated that curcumin causes significant potentiation of the function of α7-nAChRs expressed in Xenopus oocytes. In this study, we conducted in vivo experiments to assess the role of the α7-nAChR on the protective effects of curcumin in an animal model of PD. Intra-striatal injection of 6-hydroxydopmine (6-OHDA) was used to induce Parkinsonism in rats. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. The intraperitoneal administration of the α7-nAChR-selective antagonist methyllycaconitine (1 µg/kg) reversed the neuroprotective effects of curcumin in terms of both animal behavior and TH immunoreactivity. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism.

Neuroprotective Effects of Thymol, a Dietary Monoterpene Against Dopaminergic Neurodegeneration in Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD), a multifactorial movement disorder that involves progressive degeneration of the nigrostriatal system affecting the movement ability of the patient. Oxidative stress and neuroinflammation both are shown to be involved in the etiopathogenesis of PD. The aim of this study was to evaluate the therapeutic potential of thymol, a dietary monoterpene phenol in rotenone (ROT)-induced neurodegeneration in rats that precisely mimics PD in humans. Male Wistar rats were injected ROT at a dose of 2.5 mg/kg body weight for 4 weeks, to induce PD. Thymol was co-administered for 4 weeks at a dose of 50 mg/kg body weight, 30 min prior to ROT injection. The markers of dopaminergic neurodegeneration, oxidative stress and inflammation were estimated using biochemical assays, enzyme-linked immunosorbent assay, western blotting and immunocytochemistry. ROT challenge increased the oxidative stress markers, inflammatory enzymes and cytokines as well as caused significant damage to nigrostriatal dopaminergic system of the brain. Thymol treatment in ROT challenged rats appears to significantly attenuate dopaminergic neuronal loss, oxidative stress and inflammation. The present study showed protective effects of thymol in ROT-induced neurotoxicity and neurodegeneration mediated by preservation of endogenous antioxidant defense networks and attenuation of inflammatory mediators including cytokines and enzymes.

Development of Nonviral Vectors Targeting the Brain as a Therapeutic Approach For Parkinson's Disease and Other Brain Disorders.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.

Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone.

BACKGROUND: Parkinson disease (PD) is a movement disorder affecting 1 % of people over the age of 60. The etiology of the disease is unknown; however, accumulating evidence suggests that mitochondrial defects, oxidative stress, and neuroinflammation play important roles in developing the disease. Current medications for PD can only improve its symptoms, but are unable to halt its progressive nature. Although many therapeutic approaches are available, new drugs are urgently needed for the treatment of PD. Thus, the present study was undertaken to investigate the neuroprotective potential of nerolidol, a sesquiterpene alcohol, on a rotenone-induced experimental model of PD, where male Wistar rats intraperitoneally received rotenone (ROT) at a dose of 2.5 mg/kg of body weight once daily for 4 weeks. RESULTS: Nerolidol, which has antioxidant and anti-inflammatory properties, was injected intraperitoneally at 50 mg/kg of body weight, once daily for 4 weeks, and at 30 min prior to ROT administration. ROT administration significantly reduced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and the level of the antioxidant tripeptide glutathione (GSH). Moreover, ROT increased the levels of the lipid peroxidation product malondialdehyde (MDA), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), and inflammatory mediators (COX-2 and iNOS) in rat brain tissues. Immunostaining of brain tissue sections revealed a significant increase in the number of activated astrocytes (GFAP) and microglia (Iba-1), along with the concomitant loss of dopamine (DA) neurons in the substantia nigra pars compacta and dopaminergic nerve fibers in the striatum of ROT-treated rats. As expected, nerolidol supplementation to ROT-injected rats significantly increased the level of SOD, CAT, and GSH, and decreased the level of MDA. Nerolidol also inhibited the release of proinflammatory cytokines and inflammatory mediators. Finally, nerolidol treatment prevented ROT-induced glial cell activation and the loss of dopaminergic neurons and nerve fibers, and ultimately attenuated ROT-induced dopaminergic neurodegeneration. CONCLUSION: Our findings are the first to show that the neuroprotective effect of nerolidol is mediated through its anti-oxidant and anti-inflammatory activities, which strongly supports its therapeutic potential for the treatment of PD.

ß-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of ß-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

1,8-cineole (eucalyptol) mitigates inflammation in amyloid Beta toxicated PC12 cells: relevance to Alzheimer's disease.

Inflammatory process has a fundamental role in the pathogenesis of Alzheimer's disease and insoluble amyloid beta deposits and neurofibrillary tangles provide the obvious stimuli for inflammation. The present study demonstrate the effect of pretreatment of 1,8-cineole (Cin) on inflammation induced by Aß(25-35) in differentiated PC12 cells. The cells were treated with Cin at different doses for 24 h and then replaced by media containing Aß(25-35) for another 24 h. The cell viability was decreased in Aß(25-35) treated cells which was significantly restored by Cin pretreatment. Cin successfully reduced the mitochondrial membrane potential, ROS and NO levels in Aß(25-35) treated cells. Cin also lowered the levels of proinflammatory cytokines TNF-α, IL-1ß and IL-6 in Aß(25-35) treated cells. Moreover, Cin also succeeded in lowering the expression of NOS-2, COX-2 and NF-κB. This study suggests the protective effects of Cin on inflammation and provides additional evidence for its potential beneficial use in therapy as an anti-inflammatory agent in neurodegenerative disease.

Sesamol: A Phenolic Compound of Health Benefits and Therapeutic Promise in Neurodegenerative Diseases.

Sesamol, one of the key bioactive ingredients of sesame seeds (Sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review.

Centella asiatica attenuates the neurobehavioral, neurochemical and histological changes in transient focal middle cerebral artery occlusion rats.

Centella asiatica has been used as psychoactive and antioxidant herbal medicine since ancient time. The present study was design to evaluate the preventive role of ethanolic extract of C. asiatica in middle cerebral artery occlusion (MCAO) in rats. Male Wistar rats were gavaged orally with C. asiatica extract (100, 200 and 300 mg/kg body weight once daily) for 21 days and thereafter subjected to right MCAO for 2 h followed by 22-h reperfusion. Brain injury was evaluated by 2,3,5-triphenyltetrazolium chloride and hematoxylin and eosin staining. Behavioural outcomes as neurological deficit, rota rod test, and grip strength were assessed. In addition, lipid peroxidation, enzymatic and non enzymatic antioxidants were analyzed to assess the oxidative stress. Our results revealed that C. asiatica administration greatly improved neurobehavioral activity and diminished infarction volume along with the restored histological morphology of brain in MCAO rats. Furthermore, supplementation with this extract to MCAO group has reduced the level of thiobarbituric acid reactive species, restored glutathione content and augmented the activities of antioxidant enzymes-catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and superoxide dismutase in a dose-dependent manner in ischemic rats. The remarkable antioxidant activity of C. asiatica may be attributed to its bioactive triterpenes, asiatic acid, asiaticoside, madecassic acid and madecosside and may be translated to clinical level for prevention of ischemic stroke.

Taurine ameliorates neurobehavioral, neurochemical and immunohistochemical changes in sporadic dementia of Alzheimer's type (SDAT) caused by intracerebroventricular streptozotocin in rats.

Oxidative loads in the brain are involved in age related impairments like learning and memory as well as neurodegeneration. Taurine, the most abundant free amino acid in humans has many potential health benefits through its anti-oxidant and anti-inflammatory properties. Therefore, we investigated the neuroprotective potential of taurine on oxidative stress, neuronal loss and memory impairments in streptozotocin model of cognitive impairments in rats. The cognitive impairment was developed by giving single intracerebroventricular (ICV) injection of streptozotocin (STZ) 3 mg/kg body weight bilaterally. An increased latency and path length was observed in ICV-STZ group animals as compared to sham group animals and these were inhibited significantly in STZ group pre-treated with taurine (50 mg/kg body weight orally once daily for 15 days). Moreover, the significantly depleted content of GSH and elevated level of thiobarbituric acid reactive substances (TBARS) in ICV-STZ group animals were protected significantly with pre-treatment of taurine. The activity of antioxidant enzymes, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase was decreased in STZ group as compared to sham group and pre-treatment of STZ group with taurine has protected their activities significantly. Furthermore, the increased activity of acetylcholine esterase and decreased expression of choline acetyl transferase were attenuated by the pre-treatment of taurine. Taurine also protected the morphology of the hippocampal pyramidal neurons. This study concludes that the prophylactic intervention of taurine may be used to prevent the deterioration of cognitive functions and neurobehavioral activities, often associated with the generation of free radicals.

Azadirachta indica mitigates behavioral impairments, oxidative damage, histological alterations and apoptosis in focal cerebral ischemia-reperfusion model of rats.

Azadirachta indica Linn. (Meliaceae) has been used from ancient times as a remedy for various ailments. The present study was designed to investigate the antioxidant and anti-apoptotic properties of A. indica seed extract (ASE) in transient middle cerebral artery occlusion (MCAO) rat model. Antioxidant potential of ASE was determined in vitro. Further, ASE was evaluated against neurological deficits, histological alterations (TTC, CV and H&E) and oxidative damage (TBARS, GSH and nitrite) in MCAO rats. Moreover, caspase-3 and -9 were analyzed to evaluate the anti-apoptotic activity of ASE. ASE has shown potent in vitro reducing power (126.2 mg AsAE/g extract) and free radical scavenging activities (DPPH 171.0 and NO 176.0 µg/ml). Furthermore, ASE inhibited oxidative stress and decreased the activities of caspase-3 (26.7 %, p < 0.05) and caspase-9 (31.2 %, p < 0.01) thus, reduced neuronal loss in MCAO rats. Our data revealed that ASE has potent antioxidant and anti-apoptotic properties, and may be explored for its active constituents against neurodegenerative diseases.

Neuroprotective Potential and Underlying Pharmacological Mechanism of Carvacrol for Alzheimer's and Parkinson's Diseases.

The phytochemicals have antioxidant properties to counter the deleterious effects of oxidative stress in the central nervous system and can be a promising drug candidate for neurodegenerative diseases. Among various phytochemicals, constituents of spice origin have recently received special attention for neurodegenerative diseases owing to their health benefits, therapeutic potential, edible nature, and dietary accessibility and availability. Carvacrol, a phenolic monoterpenoid, has garnered attention in treating and managing various human diseases. It possesses diverse pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and anticancer. Alzheimer's disease (AD) and Parkinson's disease (PD) are major public health concerns that place a significant financial burden on healthcare systems worldwide. The global burden of these diseases is expected to increase in the next few decades owing to increasing life expectancies. Currently, there is no cure for neurodegenerative diseases, such as AD and PD, and the available drugs only give symptomatic relief. For a long time, oxidative stress has been recognized as a primary contributor to neurodegeneration. Carvacrol enhances memory and cognition by modulating the effects of oxidative stress, inflammation, and Aß25-35- induced neurotoxicity in AD. Moreover, it also reduces the production of reactive oxygen species and proinflammatory cytokine levels in PD, which further prevents the loss of dopaminergic neurons in the substantia nigra and improves motor functions. This review highlights carvacrol's potential antioxidant and anti-inflammatory properties in managing and treating AD and PD.

Unveiling the mechanisms of neuropathic pain suppression: perineural resiniferatoxin targets Trpv1 and beyond.

Neuropathic pain arises from damage or disorders affecting the somatosensory system. In rats, L5 nerve injury induces thermal and mechanical hypersensitivity/hyperalgesia. Recently, we demonstrated that applying resiniferatoxin (RTX) directly on uninjured L3 and L4 nerves alleviated thermal and mechanical hypersensitivity resulting from L5 nerve injury. Herein, using immunohistochemistry, Western blot, and qRT-PCR techniques, we reveal that perineural application of RTX (0.002%) on the L4 nerve substantially downregulated the expression of its receptor (Trpv1) and three different voltage-gated ion channels (Nav1.9, Kv4.3, and Cav2.2). These channels are found primarily in small-sized neurons and show significant colocalization with Trpv1 in the dorsal root ganglion (DRG). However, RTX treatment did not affect the expression of Kv1.1, Piezo2 (found in large-sized neurons without colocalization with Trpv1), and Kir4.1 (localized in satellite cells) in the ipsilateral DRGs. Furthermore, RTX application on L3 and L4 nerves reduced the activation of c-fos in the spinal neurons induced by heat stimulation. Subsequently, we investigated whether applying RTX to the L3 and L4 nerves 3 weeks before the L5 nerve injury could prevent the onset of neuropathic pain. Both 0.002 and 0.004% concentrations of RTX produced significant analgesic effects, while complete prevention of thermal and mechanical hypersensitivity required a concentration of 0.008%. Importantly, this preventive effect on neuropathic manifestations was not associated with nerve degeneration, as microscopic examination revealed no morphological changes. Overall, this study underscores the mechanisms and the significance of perineural RTX treatment applied to adjacent uninjured nerves in entirely preventing nerve injury-induced neuropathic pain in humans and animals.

Catechin hydrate ameliorates redox imbalance and limits inflammatory response in focal cerebral ischemia.

Epidemiologic studies have shown that foods rich in polyphenols, such as flavonoids, can lower the risk of ischemic disease; however, the mechanism of protection has not been clearly investigated. In this study, we hypothesized that pretreatment effect of catechin hydrate (CH) on functional outcome, neuronal damage and on secondary injuries in the ischemic brain of rats. To test this hypothesis, male Wistar rats were pretreated with CH (20 mg/kg b.wt) for 21 days and then subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. After 2 h MCAO/22 h reperfusion, neurological deficit, infarct sizes, activities of antioxidant enzymes and cytokines level were measured. Immunohistochemistry and western blot were used to analyse the expression of glial fibrillary acidic protein (GFAP), inducible nitric oxide (iNOS) and NF-kB in ischemic brain. The administration of CH showed marked reduction in infarct size, reduced the neurological deficits, suppressed neuronal loss and downregulate the iNOS, GFAP and NF-kB expression in MCAO rats. A significantly depleted activity of antioxidant enzymes and content of glutathione in MCAO group were protected significantly in MCAO group pretreated with CH. Conversely, the elevated level of thiobarbituric acid reactive species and cytokines in MCAO group was attenuated significantly in CH pretreated group when compared with MCAO group. The results indicated that CH protected the brain from damage caused by MCAO, and this effect may be through downregulation of NF-kB expression.

Edaravone ameliorates oxidative stress associated cholinergic dysfunction and limits apoptotic response following focal cerebral ischemia in rat.

Stroke is a life-threatening disease with major cause of mortality and morbidity worldwide. The neuronal damage following cerebral ischemia is a serious risk to stroke patients. Oxidative stress and apoptotic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The objective of this study was to test the hypothesis that administration of edaravone (Edv) maintains antioxidant status in brain, improves the cholinergic dysfunction and suppresses the progression of apoptosis response in rat. To test this hypothesis, male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) of 2 h followed by reperfusion for 22 h. Edv was administered (10 mg/kg bwt) intraperitoneally 30 min before the onset of ischemia and 1 h after reperfusion. After reperfusion, rats were tested for neurobehavioral activities and were sacrificed for the infarct volume, estimation of oxidative damage markers. Edv treatment significantly reduced ischemic lesion volume, improved neurological deficits, contended oxidative loads, and suppressed apoptotic damage. In conclusion, treatment with Edv ameliorated the neurological and histological outcomes with elevated endogenous anti-oxidants status as well as reduced induction of apoptotic responses in MCA occluded rat. We theorized that Edv is among the pharmacological agents that reduce free radicals and its associated cholinergic dysfunction and apoptotic damage and have been found to limit the extent of brain damage following stroke.

Attenuation of Aß-induced neurotoxicity by thymoquinone via inhibition of mitochondrial dysfunction and oxidative stress.

Beta-amyloid (Aß) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and compounds that can prevent pathways of Aß-induced neurotoxicity may be potential therapeutic agents for treatment of AD. This study examined the hypothesis that thymoquinone (TQ) would reduce oxidative stress and mitochondrial dysfunction in differentiated pheochromocytoma (PC 12) cells exposed to Aß fragment 25-35 (Aß(25-35)). To test this hypothesis, Aß was used to induce an in vitro model of AD in differentiated PC 12 cell line of rat. After 24 h of exposure with Aß(25-35), a significant reduction in cell viability and mitochondrial membrane potential (MMP) was observed. In addition, a significant elevation in the TBARS content and nitric oxide (NO) and activity of acetylcholine esterase (AChE) was observed which was restored significantly by TQ pretreatment. Furthermore, TQ also ameliorated glutathione and its dependent enzymes (glutathione peroxidase, glutathione reductase) which were depleted by Aß(25-35) in PC 12 cells. These results were supported by the immunocytochemical finding that has shown protection of cells by TQ from noxious effects of Aß(25-35). These results indicate that TQ holds potential for neuroprotection and may be a promising approach for the treatment of neurodegenerative disorders including AD.

Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model.

The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05-0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1ß, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death.

Ocimum sanctum attenuates oxidative damage and neurological deficits following focal cerebral ischemia/reperfusion injury in rats.

Stroke is an enormous public health problem with an imperative need for more effective therapy. Free radicals have been reported to play a role in the expansion of ischemic brain lesions, and the effect of free radical scavengers is still under debate. The present study investigated the neuroprotective effect of Ocimum sanctum (OS) to reduce brain injury after middle cerebral artery occlusion (MCAO). Male Wistar rats were subjected to MCAO for 2 h and reperfused for 22 h. The administration of OS (200 mg/kg bwt., orally) once daily for 15 days before MCAO showed marked reduction in infarct size, reduced the neurological deficits, and suppressed neuronal loss in MCAO rats. A significantly depleted activity of antioxidant enzymes and content of glutathione in MCAO group were protected significantly in MCAO group pretreated with OS. Conversely, the elevated level of thiobarbituric acid-reactive substances (TBARS) in MCAO group was attenuated significantly in OS-pretreated group when compared with MCAO group. Consequently, OS pretreatment may reduce the deterioration caused by free radicals, and thus may used to prevent subsequent behavioral, biochemical and histopathological changes that transpire during cerebral ischemia. This finding reflects that supplementation of OS intuitively by reasonable and understandable treatment effectively ameliorates the cerebral ischemia-induced oxidative damage.

Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain.

Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat's hind paw on the neuropathic pain induced by L5 nerve injury. The results showed that intraplantar injection of RTX (0.002%, 100 µL) (1) completely reversed the development of chronic thermal and mechanical hypersensitivity; (2) completely prevented the development of nerve-injury-induced thermal and mechanical hypersensitivity when applied one week earlier; (3) caused downregulation of nociceptive pain markers, including TRPV1, IB4 and CGRP, and upregulation of VIP in the ipsilateral dorsal horn of spinal cord and dorsal root ganglion (DRG) immunohistochemically and a significant reduction in the expression of TRPV1 mRNA and protein in the ipsilateral DRG using Western blot and qRT-PCR techniques; (4) caused downregulation of PGP 9.5- and CGRP-immunoreactivity in the injected skin; (5) produced significant suppression of c-fos expression, as a neuronal activity marker, in the spinal neurons in response to a second intraplantar RTX injection two weeks later. This work identifies the ability of cutaneous injection of RTX to completely alleviate and prevent the development of different types of neuropathic pain in animals and humans.