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Abstract: Ethnopharmacological relevance: The present study investigates the protective effects of water extract of ginseng (Panax ginseng C.A. Meyer) against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity in SH-SY5Y human neuroblastoma cells and explores the underlying mechanisms. The approach may be used for screening therapeutic agents for degenerative disorders such as Parkinson''s disease. Materials and methods: SH-SY5Y human neuroblastoma cells were used to analyze the protective effects of water extract of ginseng (WEG) against multiple parameters such as MPP+-induced viability, oxidative injury, expression of Bax, Bcl-2, cytochrome c and cleaved caspase-3. Results: WEG exerted inhibitory effect on cell death, overproduction of ROS, elevated Bax/Bcl-2 ratio, release of cytochrome c and activation of caspase-3 expression in MPP+-treated SH-SY5Y cells. Conclusions: WEG exhibited significant protective effects against MPP+-induced cytotoxicity in SH-SY5Y cells possibly through the suppression of ROS generation and the inhibition of mitochondria-dependent apoptotic pathway. [Copyright &y& Elsevier]

Abstract: Vascular endothelial growth factor (VEGF), a specific pro-angiogenic peptide, has shown neuroprotective effects in the Parkinson’s disease (PD) models, but the underlying mechanisms remain elusive. In this study, the neuroprotective properties of VEGF on 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity in primary cerebellar granule neurons were investigated. Pretreatment of VEGF prevented MPP+-induced neuronal apoptosis in a concentration- and time-dependent manner. And this prevention was blocked by PTK787/ZK222584, a VEGF receptor-2 specific inhibitor. Both inhibition of the Akt pathway and activation of the extracellular signal-regulated kinase (ERK) pathway contribute to MPP+-induced neuronal apoptosis. VEGF reversed the inhibition of phosphoinositide 3-kinase (PI3-K)/Akt pathway caused by MPP+, but further enhanced the activation of ERK induced by MPP+. Interestingly, VEGF and PD98059 (an ERK kinase inhibitor) play a synergistic role in protecting neurons from MPP+-induced toxicity. Collectively, these findings suggest that the PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis. This finding offers not only a new and clinically significant modality as to how VEGF exerts its neuroprotective effects but also a novel therapeutic strategy for PD by differentially regulating PD-associated signaling pathways. [Copyright &y& Elsevier]

Highlights • Ghrelin(1–7)-NH 2 (i.c.v.) induced antinociception in acute pain in mice. • Ghrelin(1–7)-NH 2 induced antinociception through GHS-R1α and opioid receptors. • Ghrelin(1–7)-NH 2 (i.c.v.) was distributed at the dorsal 3rd ventricle and hippocampus. • mRNA and protein levels of δ -opioid peptide and receptor were increased in the test. Abstract Ghrelin(1–7)-NH 2 is the active N-terminal hepta-peptide of ghrelin as an agonist at the ghrelin receptor GHS-R1α. The biological functions of ghrelin(1–7)-NH 2 have not been well investigated. Therefore in this study, we were interested in exploring the effects and molecular mechanisms of ghrelin(1–7)-NH 2 in pain modulation at the supraspinal level using the tail withdrawal test in mice. Intracerebroventricular (i.c.v.) injection of ghrelin(1–7)-NH 2 (0.002, 0.02, 0.2 and 2 nmol/kg) induced a dose- and time-related antinociceptive effect. This antinociceptive effect was fully antagonized by co-injection with the GHS-R1α antagonist [D-Lys3]-GHRP-6, indicating that this effect induced by ghrelin(1–7)-NH 2 was mediated through the activation of GHS-R1α. Interestingly, naloxone, β-funaltrexamine, naloxonazine, and naltrindole, but not nor-binaltorphimine, could also antagonize the antinociceptive effect markedly, suggesting that OPRM (primary μ 1 subtype) and OPRD were involved in the antinociceptive response induced by ghrelin(1–7)-NH 2. Furthermore, the qRT-PCR and Western blot results indicated that both mRNA and protein levels of PENK and OPRD were up-regulated significantly. Using the fluorescence labeling method, our results showed that ghrelin(1–7)-NH 2 (i.c.v.) was mainly distributed at the dorsal 3rd ventricle and hippocampus where there are regions with high expressions of ghrelin, GHS-R1α and ORs. All these results indicated that ghrelin(1–7)-NH 2 initially activated the GHS-R1α, then activated the OPRM, as well as increased the release of endogenous PENK to activate of OPRD to produce antinociception. These results contributed to understanding the mechanisms of antinociception induced by ghrelin(1–7)-NH 2. Furthermore, ghrelin(1–7)-NH 2 as the active fragment of ghrelin may be a promising peptide for developing new analgesic drugs. [ABSTRACT FROM AUTHOR]

Background and Purpose: SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP(+) )-induced neurotoxicity and further explored the underlying mechanisms.Experimental Approach: MPP(+) -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms.Key Results: SU4312 unexpectedly prevented MPP(+) -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC(50) value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS.Conclusions and Implication: SU4312 exhibited neuroprotection against MPP(+) at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity. [ABSTRACT FROM AUTHOR]

Background and Purpose SU4312, a potent and selective inhibitor of VEGF receptor-2 ( VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion ( MPP+)-induced neurotoxicity and further explored the underlying mechanisms. Experimental Approach MPP+-treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. Key Results SU4312 unexpectedly prevented MPP+-induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. Conclusions and Implication SU4312 exhibited neuroprotection against MPP+ at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson’s disease (PD). In this study, we investigated the neuroprotective effect of tacrine–ferulic acid dimers linked by an alkylenediamine side chain (TnFA, n =2−7), a series of novel acetylcholinesterase inhibitors, against 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells. Among these dimers, pre-treatment of tacrine(2)–ferulic acid (T2FA, 3−30μM) attenuated 6-OHDA-induced apoptosis in a concentration-dependent manner. The activations of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) were observed after the treatment of 6-OHDA. Both SB415286 (an inhibitor of GSK3β) and PD98059 (an inhibitor of ERK kinase) reduced the neurotoxicity induced by 6-OHDA, indicating that GSK3β and ERK are involved in 6-OHDA-induced apoptosis. T2FA was able to inhibit the activation of GSK3β, but not ERK, in an Akt-dependent manner. Furthermore, LY294002, a phosphoinositide 3-kinase inhibitor, abolished the neuroprotective effect of T2FA. Collectively, these results suggest that T2FA prevents 6-OHDA-induced apoptosis possibly by activating the Akt pathway in PC12 cells. [Copyright &y& Elsevier]

Abstract: The activation of N-methyl-d-aspartate (NMDA) receptors by excessive release of glutamate is involved in the pathogenesis of ischemic stroke. Thus the NMDA receptor has become an attractive therapeutic target for the development of neuroprotectants, especially from antagonists with moderate to low affinity. In the current study, NMDA receptor blockage and neuroprotective effects of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor derived from a naturally occurring monomeric analog huperzine A, were investigated in vitro and in vivo. In primary rat cerebellar granule neurons, B12H (0.1nM to 1μM) prevented glutamate-induced apoptosis in a concentration- and time-dependent manner. Receptor-ligand binding analysis showed that B12H competed with [3H]MK801 with a Ki value of 7.7μM. In the 2-hour middle cerebral artery occlusion rat model, B12H (0.4 and 0.8mg/kg, 30min before-ischemia and 15min post-ischemia, i.p.) significantly attenuated ischemia-induced apoptosis in the penumbra region, improved neurological behavior impairment, and decreased cerebral infarct volume, cerebral edema and neuronal apoptosis in the stroke model. Together, these results showed that B12H moderately blocks NMDA receptors at MK801 site and exerts neuroprotection against excitotoxic and ischemic insults in vitro and in vivo. Combined with our previous publications, we conjecture that B12H might exert neuroprotection via acting on multiple targets. [Copyright &y& Elsevier]