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Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced mouse model of PD. KRGE (37.5 mg/kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase–immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2–related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood–brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood–brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD. Keywords: Korean Red Ginseng extract, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Multitarget effect

Background: Depression is one of the most commonly diagnosed neuropsychiatric diseases, but the underlying mechanism and medicine are not well-known. Although Panax ginseng has been reported to exert protective effects in various neurological studies, little information is available regarding its antidepressant effects. Methods: Here, we examined the antidepressant effect and underlying mechanism of P. ginseng extract (PGE) in a chronic restraint stress (CRS)-induced depression model in mice. Results: Oral administration of PGE for 14 d decreased immobility (depression-like behaviors) time in forced swim and tail suspended tests after CRS induction, which corresponded with attenuation of the levels of serum adrenocorticotropic hormone and corticosterone, as well as attenuated c-Fos expression in the amygdala. PGE enhanced messenger RNA expression level of brain-derived neurotrophic factor but ameliorated microglial activation and neuroinflammation (the level of messenger RNA and protein expression of cyclooxygenase-2 and inducible nitric oxide synthase) in the amygdala of mice after CRS induction. Interestingly, 14-d treatment with celecoxib, a selective cyclooxygenase-2 inhibitor, and Nω-nitro-L-arginine methyl ester hydrochloride, a selective inducible nitric oxide synthase inhibitor, attenuated depression-like behaviors after CRS induction. Additionally, PGE inhibited the upregulation of the nuclear factor erythroid 2 related factor 2 and heme oxygenase-1 pathways. Conclusion: Taken together, our findings suggest that PGE exerts antidepressant-like effect of CRS-induced depression by antineuroinflammatory and antioxidant (nuclear factor erythroid 2 related factor 2/heme oxygenase-1 activation) activities by inhibiting the hypothalamo-pituitary-adrenal axis mechanism. Further studies are needed to evaluate the potential of components of P. ginseng as an alternative treatment of depression, including clinical trial evaluation.

It has been previously indicated that gintonin, which is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand, restores memory dysfunctions in an APPswe/PSEN-1 double-transgenic mouse model of Alzheimer's disease (AD Tg mice) by attenuating β-amyloid plaque deposition, recovering cholinergic dysfunctions and upregulating hippocampal neurogenesis in the cortex and hippocampus. Although β-amyloid plaque depositions in AD is accompanied with disruptions of brain microvessels, including the brain-blood barrier (BBB), it is unknown whether gintonin exerts protective effects on brain microvascular dysfunctions in AD Tg mice. In the present study, the effects of gintonin-enriched fraction (GEF) on the changes in β-amyloid plaque depositions, brain permeability of Evans blue, and microvascular junctional proteins were investigated in AD Tg mice. Long-term oral administration of GEF reduced β-amyloid plaque depositions in the cortex and hippocampus of AD Tg mice. GEF treatment also reduced the permeability of Evans blue through BBB and decreased immunoreactivity of platelet endothelial cell adhesion molecule-1 (a marker of BBB disruption) in the cortex and hippocampus of AD Tg mice in a dose-dependent manner. However, GEF elevated the protein expression of occludin, claudin-5 and zonula occludens-1, which are tight-junction proteins. The present results demonstrated that long-term oral GEF treatment not only attenuates β-amyloid plaque depositions in the brain but also exhibits protective effects against microvascular disruptions in AD Tg mice. Finally, GEF exhibits anti-AD effects through attenuation of β-amyloid plaque depositions and protection against brain microvascular damage in an AD animal model.

A traditional herbal prescription Kyung-Ok-Ko (KOK), composed of Rehmannia glutinosa Liboschitz var. purpurae, Lycium chinense, Aquilaria agallocha, Poria cocos, Panax ginseng, and honey, has been widely used in Oriental medicine as an invigorant for age-related diseases, such as amnesia and stroke. However, the beneficial value of KOK on uterine dysfunction related to hyperandrogenism is largely unknown. We investigated the effect of KOK (2.0 g/kg/day, per os) on endometrial abnormalities in a dehydroepiandrosterone (DHEA, subcutaneous)-induced polycystic ovary syndrome (PCOS) rat model. Preadministration of KOK significantly (p

Woohwangchungsimwon (WCW) is an oriental medicine that has been extensively prescribed in Asia to patients with apoplexy, high blood pressure, acute/chronic convulsion, and so on. However, the potential therapeutic value of WCW in treating the pathologic brain has not yet been fully investigated. In the present study, we evaluated whether WCW has beneficial effects on kainic acid (KA)-induced excitotoxicity. An intraperitoneal injection of KA (40 mg/kg) and an intracerebroventricular injection of KA (0.2 μg) produced typical seizure behavior and neuronal cell death in the CA1 and CA3 pyramidal layers of the hippocampus, respectively. However, the systemic administration of WCW significantly attenuated the seizure behavior and neuronal cell death. WCW was found to exert the best protective effect when it was administrated 2 hours before a KA injection. Moreover, this WCW-induced neuroprotection was accompanied by a reduction in microglia activation and tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxyganase-2 in the hippocampus. These results suggest that WCW has therapeutic potential to suppress KA-induced pathogenesis in the brain by inhibiting inflammation.

Kyung-Ok-Ko (KOK), a traditional multi-herbal medicine, has been widely used in Oriental medicine as a restorative that can enforce vitality of whole organs and as a medicine that can treat age-related symptoms including lack of vigor and weakened immunity. However, the beneficial effect of KOK on neurological diseases such as Parkinson's diseases (PD) is largely unknown. Thus, the objective of this study was to examine the protective effect of KOK on neurotoxicity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pre-treatment with KOK at 1 or 2 g/kg/day (p.o.) showed significant mitigating effects on neurological dysfunction (motor and welfare) based on pole, rotarod, and nest building tests. It also showed effects on survival rate. These positive effects of KOK were related to inhibition of loss of tyrosine hydroxylase-positive neurons, reduction of MitoSOX activity, increased apoptotic cells, microglia activation, and upregulation of inflammatory factors [interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide], and reduced blood-brain barrier (BBB) disruption in the substantia nigra pars compacta (SNpc) and/or striatum after MPTP intoxication. Interestingly, these effects of KOK against MPTP neurotoxicity were associated with inhibition of phosphorylation of mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways along with up-regulation of nuclear factor erythroid 2-related factor 2 pathways in SNpc and/or striatum. Collectively, our findings suggest that KOK might be able to mitigate neurotoxicity in MPTP-induced mouse model of PD via multi-effects, including anti-neuronal and anti-BBB disruption activities through its anti-inflammatory and anti-oxidative activities. Therefore, KOK might have potential for preventing and/or treating PD.

Complete animal models investigating the pathogenesis and treatment of polycystic ovarian syndrome (PCOS) are not completely established. Although dehydroepiandrosterone (DHEA)-induced pre-pubertal rat model for PCOS has been widely used, the model exhibits weaknesses such as decreased ovary weight. Here, we report an innovative DHEA-induced PCOS model that addresses limitations of the pre-pubertal model. The 21-day-old (pre-pubertal) and 42-day-old (post-pubertal) female rats were subcutaneously injected with DHEA (60 mg/kg body weight) daily for up to 20–30 days. The post-pubertal model showed a steady increase in ovary weight and the number of ovarian cysts as well as uterine weight and thickness, which may be key features of PCOS, compared with the pre-pubertal model. Therefore, a post-pubertal PCOS model induced by DHEA may be an improved model to investigate the etiology of PCOS and development of therapeutic interventions.

Background Beneficial effects of Korean Red Ginseng (KRG) on polycystic ovarian syndrome (PCOS) remains unclear. Methods We examined whether pretreatment (daily from 2 hours before PCOS induction) with KRG extract in water (KRGE; 75 and 150 mg/kg/day, p.o.) could exert a favorable effect in a dehydroepiandrosterone (DHEA)-induced PCOS rat model. Results Pretreatment with KRGE significantly inhibited the elevation of body and ovary weights, the increase in number and size of ovarian cysts, and the elevation of serum testosterone and estradiol levels induced by DHEA. Pretreatment with KRGE also inhibited macrophage infiltration and enhanced mRNA expression levels of chemokines [interleukin (IL)-8, monocyte chemoattractant protein-1), proinflammatory cytokines (IL-1β, IL-6), and inducible nitric oxide synthase in ovaries induced by DHEA. It also prevented the reduction in mRNA expression of growth factors (epidermal growth factor, transforming growth factor-beta (EGF, TGF-β)) related to inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell pathway and stimulation of the nuclear factor erythroid–derived 2-related factor 2 pathway. Interestingly, KRGE or representative ginsenosides (Rb1, Rg1, and Rg3(s)) inhibited the activity of inflammatory enzymes cyclooxygenase-2 and iNOS, cytosolic p-IkB, and nuclear p–nuclear factor kappa-light-chain-enhancer of activated B in lipopolysaccharide-induced RAW264.7 cells, whereas they increased nuclear factor erythroid–derived 2-related factor 2 nuclear translocation. Conclusion These results provide that KRGE could prevent DHEA-induced PCOS via antiinflammatory and antioxidant activities. Thus, KRGE may be used in preventive and therapeutic strategies for PCOS-like symptoms.

Gintonin (GT), a ginseng-derived lysophosphatidic acid receptor ligand, regulates various cellular effects and represses inflammation. However, little is known about the potential value of GT regarding inflammation in the neurodegenerative diseases, such as Huntington’s disease (HD). In this study, we investigated whether GT could ameliorate the neurological impairment and striatal toxicity in cellular or animal model of HD. Pre-, co-, and onset-treatment with GT (25, 50, or 100 mg/kg/day, p.o.) alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid (3-NPA). Pretreatment with GT also attenuated mitochondrial dysfunction i.e. succinate dehydrogenase and MitoSOX activities, apoptosis, microglial activation, and mRNA expression of inflammatory mediators i.e. IL-1β, IL-6, TNF-α, COX-2, and iNOS in the striatum after 3-NPA-intoxication. Its action mechanism was associated with lysophosphatidic acid receptors (LPARs) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activations and the inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. These beneficial effects of GT were neutralized by pre-inhibiting LPARs with Ki16425 (a LPAR1/3 antagonist). Interestingly, GT reduced cell death and mutant huntingtin (HTT) aggregates in STHdh cells. It also mitigated neurological impairment in mice with adeno-associated viral (AAV) vector serotype DJ-mediated overexpression of N171-82Q-mutant HTT in the striatum. Taken together, our findings firstly suggested that GT has beneficial effects with a wide therapeutic time-window in 3-NPA-induced striatal toxicity by antioxidant and anti-inflammatory activities through LPA. In addition, GT exerts neuroprotective effects in STHdh cells and AAV vector-infected model of HD. Thus GT might be an innovative therapeutic candidate to treat HD-like syndromes.

Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. HD is caused by an expansion of CAG repeats in the huntingtin (HTT) gene in various areas of the brain including striatum. There are few suitable animal models to study the pathogenesis of HD and validate therapeutic strategies. Recombinant adeno-associated viral (AAV) vectors successfully transfer foreign genes to the brain of adult mammalians. In this article, we report a novel mouse model of HD generated by bilateral intrastriatal injection of AAV vector serotype DJ (AAV-DJ) containing N171-82Q mutant HTT (82Q) and N171-18Q wild type HTT (18Q; sham). The AAV-DJ-82Q model displayed motor dysfunctions in pole and rotarod tests beginning 4 weeks after viral infection in juvenile mice (8 weeks after birth). They showed behaviors reflecting neurodegeneration. They also showed increased apoptosis, robust glial activation and upregulated representative inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), mediators (cyclooxygenase-2 and inducible nitric oxide synthase) and signaling pathways (nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3)) in the striatum at 10 weeks after viral infection (14 weeks after birth) via successful transfection of mutant HTT into neurons, microglia, and astrocytes in the striatum. However, little evidence of any of these events was found in mice infected with the AAV-DJ-18Q expressing construct. Intrastriatal injection of AAV-DJ-82Q might be useful as a novel in vivo model to investigate the biology of truncated N-terminal fragment (N171) in the striatum and to explore the efficacy of therapeutic strategies for HD.

Gintonin is a ginseng-derived lysophosphatidic acid receptor (LPAR) ligand. Although previous in vitro and in vivo studies demonstrated the therapeutic role of gintonin against Alzheimer’s disease, the neuroprotective effects of gintonin in Parkinson’s disease (PD) are still unknown. We investigated whether gintonin (50 and 100 mg/kg/day, p.o., daily for 12 days) had neuroprotective activities against neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pre-administration of 100 mg/kg gintonin displayed significantly ameliorating effects in neurological disorders (motor and welfare) as measuring using pole, rotarod, and nest building tests, and in the survival rate. These effects were associated to the reduction of the loss of tyrosine hydroxylase–positive neurons, microglial activation, activation of inflammatory mediators (interleukin-6, tumor necrosis factor, and cyclooxygenase-2), and alteration of blood-brain barrier (BBB) integrity in the substantia nigra pars compacta and/or striatum following MPTP injection. The benefits of gintonin treatment against MPTP also included the activation of the nuclear factor erythroid 2-related factor 2 pathways and the inhibition of phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways. Interestingly, these neuroprotective effects of gintonin were blocked by LPAR1/3 antagonist, Ki16425. Overall, the present study shows that gintonin attenuates MPTP-induced neurotoxicity via multiple targets. Gintonin combats neuronal death, and acts as an anti-inflammatory and an anti-oxidant agent. It maintains BBB integrity. LPA receptors play a key role in gintonin-mediated anti-PD mechanisms. Finally, gintonin is a key agent for prevention and/or treatment of PD.

The effects of Korean red ginseng extract (KRGE) on autoimmune disorders of the nervous system are not clear. We investigated whether KRGE has a beneficial effect on acute and chronic experimental autoimmune encephalomyelitis (EAE). Pretreatment (daily from 10 days before immunization with myelin basic protein peptide) with KRGE significantly attenuated clinical signs and loss of body weight and was associated with the suppression of spinal demyelination and glial activation in acute EAE rats, while onset treatment (daily after the appearance of clinical symptoms) did not. The suppressive effect of KRGE corresponded to the messenger RNA (mRNA) expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin [IL]-1β), chemokines (RANTES, monocyte chemotactic protein-1 [MCP-1], and macrophage inflammatory protein-1α [MIP-1α]), adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and platelet endothelial cell adhesion molecule [PECAM-1]), and inducible nitric oxide synthase in the spinal cord after immunization. Interestingly, in acute EAE rats, pretreatment with KRGE significantly reduced the population of CD4(+), CD4(+)/IFN-γ(+), and CD4(+)/IL-17(+) T cells in the spinal cord and lymph nodes, corresponding to the downregulation of mRNA expression of IFN-γ, IL-17, and IL-23 in the spinal cord. On the other hand, KRGE pretreatment increased the population of CD4(+)/Foxp3(+) T cells in the spinal cord and lymph nodes of these rats, corresponding to the upregulation of mRNA expression of Foxp3 in the spinal cord. Interestingly, intrathecal pretreatment of rats with ginsenosides (Rg1 and Rb1) significantly decreased behavioral impairment. These results strongly indicate that KRGE has a beneficial effect on the development and progression of EAE by suppressing T helper 1 (Th1) and Th17 T cells and upregulating regulatory T cells. Additionally, pre- and onset treatment with KRGE alleviated neurological impairment of myelin oligodendrocyte glycoprotein(35-55)-induced mouse model of chronic EAE. These results warrant further investigation of KRGE as preventive or therapeutic strategies for autoimmune disorders, such as multiple sclerosis.

The protective and therapeutic mechanism of bee venom acupuncture (BVA) in neurodegenerative disorders is not clear. We investigated whether treatment with BVA (0.25 and 0.8 mg/kg) at the Zusanli (ST36) acupoints, located lateral from the anterior border of the tibia, has a beneficial effect in a myelin basic protein (MBP)(68-82)-induced acute experimental autoimmune encephalomyelitis (EAE) rat model. Pretreatment (every 3 days from 1 h before immunization) with BVA was more effective than posttreatment (daily after immunization) with BVA with respect to clinical signs (neurological impairment and loss of body weight) of acute EAE rats. Treatment with BVA at the ST36 acupoint in normal rats did not induce the clinical signs. Pretreatment with BVA suppressed demyelination, glial activation, expression of cytokines [interferon (IFN)-γ, IL-17, IL-17A, tumor necrosis factor-alpha (TNF-α), and IL-1β], chemokines [RANTES, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1α], and inducible nitric oxide synthase (iNOS), and activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB (p65 and phospho-IκBα) signaling pathways in the spinal cord of acute EAE rats. Pretreatment with BVA decreased the number of CD4(+), CD4(+)/IFN-γ(+), and CD4(+)/IL-17(+) T cells, but increased the number of CD4(+)/Foxp3(+) T cells in the spinal cord and lymph nodes of acute EAE rats. Treatment with BVA at six placebo acupoints (SP9, GB39, and four non-acupoints) did not have a positive effect in acute EAE rats. Interestingly, onset and posttreatment with BVA at the ST36 acupoint markedly attenuated neurological impairment in myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced chronic EAE mice compared to treatment with BVA at six placebo acupoints. Our findings strongly suggest that treatment with BVA with ST36 acupoint could delay or attenuate the development and progression of EAE by upregulating regulatory T cells and suppressing T-helper (Th) 17 and Th1 responses. These results warrant further investigation of BVA as a treatment for autoimmune disorders of the central nervous system.

The beneficial value of the stems of Schisandra chinensis (SSC) in neurological diseases is unclear. We examined whether SSC aqueous extract (SSCE) alleviates striatal toxicity in a 3-nitropropionic acid (3-NPA)-induced mouse model of Huntington's disease (HD). SSCE (75, 150, or 300 mg/kg/day, p.o.) was given daily before or after 3-NPA treatment. Pre- and onset-treatment with SSCE displayed a significant protective effect and pretreatment was more effective as assessed by neurological scores and survival rate. These effects were related to reductions in mean lesion area, cell death, succinate dehydrogenase activity, microglial activation, and protein expression of inflammatory factors including interleukin (IL)−1β, IL-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NPA treatment. Pretreatment with SSCE stimulated the nuclear factor erythroid 2-related factor 2 pathway and inhibited phosphorylation of the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways in the striatum after 3-NPA treatment. The gomisin A and schizandrin components of SSCE significantly reduced the neurological impairment and lethality induced by 3-NPA treatment. These results indicate for the first time that SSCE may effectively prevent 3-NPA-induced striatal toxicity during a wide therapeutic time window through anti-oxidative and anti-inflammatory activities. SSCE has potential value in preventive and therapeutic strategies for HD-like symptoms.

Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C18 : 2 with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD. In a previous study, we demonstrated that gintonin exerted anti-inflammatory effects via inhibition of microglial activation and proinflammatory cytokine production by immune cells and that it strongly inhibited ATX activity. In this study, we investigated whether oral administration of the gintonin-enriched fraction (GEF) could ameliorate the symptoms of 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/Nga mice. We found that oral administration of GEF to DNFB-induced AD mice for 2 weeks reduced ear swelling and AD skin index. In addition, oral administration of GEF reduced the serum levels of immunoglobulin E, histamine, interleukin-4, and interferon-γ. Histological examination showed that oral administration of GEF attenuated skin inflammation and significantly reduced eosinophil and mast cell infiltration into the skin. Moreover, oral administration of GEF not only decreased serum ATX level but also reduced serum ATX activity. The present study shows that the anti-AD effects of ginseng might be attributed to GEF-induced anti-inflammatory activity and ATX regulation.

Ginseng gintonin is an exogenous ligand of lysophosphatidic acid (LPA) receptors. Accumulating evidence shows LPA helps in rapid recovery of corneal damage. The aim of this study was to evaluate the therapeutic efficacy of gintonin in a rabbit model of corneal damage. We investigated the signal transduction pathway of gintonin in human corneal epithelium (HCE) cells to elucidate the underlying molecular mechanism. We next evaluated the therapeutic effects of gintonin, using a rabbit model of corneal damage, by undertaking histochemical analysis. Treatment of gintonin to HCE cells induced transient increases of [Ca2+]i in concentration-dependent and reversible manners. Gintonin-mediated mobilization of [Ca2+]i was attenuated by LPA1/3 receptor antagonist Ki16425, phospholipase C inhibitor U73122, inositol 1,4,5-triphosphate receptor antagonist 2-APB, and intracellular Ca2+ chelator BAPTA-AM. Gintonin facilitated in vitro wound healing in a concentration-dependent manner. When applied as an eye-drop to rabbits with corneal damage, gintonin rapidly promoted recovery. Histochemical analysis showed gintonin decreased corneal apoptosis and increased corneal cell proliferation. We demonstrated that LPA receptor activation by gintonin is linked to in vitro and in vivo therapeutic effects against corneal damage. Gintonin can be applied as a clinical agent for the rapid healing of corneal damage.

Ginsenoside-Rb1 (Rb1) has anti-inflammatory effects. However, the potential antinociceptive value of Rb1 for the treatment of acute inflammatory nociception is still unknown. In this study, we examined whether Rb1 has any antinociceptive effects on acute inflammatory nociception in Sprague Dawley rats given intrathecal (i.t.) introduction of Rb1 (2, 10, and 50 μg) 20 minutes before injection of formalin (5%, 50 μL) into the plantar surface of the hind paws. I.t. introduction of Rb1 significantly decreased nociceptive behavior during phase II (16–60 minutes), but not phase I (0–10 minutes), after formalin stimulation, corresponding to the reduced activation of c-Fos in the L4 to L5 spinal dorsal horn after formalin stimulation. Rb1 also reduced the phosphorylation of extracellular signal-regulated kinase in the neurons, but not the microglia and astrocytes. Microscopic examination of the microglia and astrocytes revealed no morphological changes due to formalin stimulation and i.t. introduction of Rb1. Interestingly, Rb1 activated the nuclear factor erythroid 2-related factor 2 pathway and inhibited nuclear factor kappa B pathways. Perspective Our findings indicate that i.t. introduction of Rb1 might effectively inhibit formalin-induced acute inflammatory nociception by inhibition of neuronal extracellular signal-regulated kinase phosphorylation, which is thought to regulate the nuclear factor erythroid 2-related factor 2 nuclear factor kappa B pathways in the spinal dorsal horn, which suggests therapeutic potential for suppression of acute inflammatory pain.

The potential neuroprotective value of sulforaphane (SFN) in Huntington's disease (HD) has not been established yet. We investigated whether SFN prevents and improves the neurological impairment and striatal cell death in a 3-nitropropionic acid (3-NP)-induced mouse model of HD. SFN (2.5 and 5.0 mg/kg/day, i.p.) was given daily 30 min before 3-NP treatment (pretreatment) and from onset/progression/peak points of the neurological scores. Pretreatment with SFN (5.0 mg/kg/day) produced the best neuroprotective effect with respect to the neurological scores and lethality among other conditions. The protective effects due to pretreatment with SFN were associated with the following: suppression of the formation of a lesion area, neuronal death, succinate dehydrogenase activity, apoptosis, microglial activation, and mRNA or protein expression of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NP treatment. Also, pretreatment with SFN activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and inhibited the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways in the striatum after 3-NP treatment. As expected, the pretreatment with activators (dimethyl fumarate and antioxidant response element inducer-3) of the Keap1-Nrf2-ARE pathway decreased the neurological impairment and lethality after 3-NP treatment. Our findings suggest that SFN may effectively attenuate 3-NP-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways and that SFN has a wide therapeutic time-window for HD-like symptoms.