We investigated the neuroprotective property of analogs of dextromethorphan (DM) in lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to identify neuroprotective drugs for Parkinson's disease (PD).In vivo studies showed that daily injections with DM analogs protected dopamine (DA) neurons in substantia nigra pars compacta and restored DA levels in striatum using two different models for PD. Of the five analogs studied, 3-hydroxymorphinan (3-HM), a metabolite of DM, was the most potent, and restored DA neuronal loss and DA depletion up to 90% of the controls. Behavioral studies showed an excellent correlation between potency for preventing toxin-induced decrease in motor activities and neuroprotective effects among the DM analogs studied, of which 3-HM was the most potent in attenuating behavioral damage. In vitro studies revealed two glia-dependent mechanisms for the neuroprotection by 3-HM. First, astroglia mediated the 3-HM-induced neurotrophic effect by increasing the gene expression of neurotrophic factors, which was associated with the increased acetylation of histone H3. Second, microglia participated in 3-HM-mediated neuroprotection by reducing MPTP-elicited reactive microgliosis as evidenced by the decreased production of reactive oxygen species. In summary, we show the potent neuroprotection by 3-HM in LPS and MPTP PD models investigated. With its high efficacy and low toxicity, 3-HM may be a novel therapy for PD. Parkinson's disease (pd) is a neurodegenerative disorder characterized by a chronic and progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNpc), leading to movement disorders including dyskinesia, resting tremor, rigidity, and gait disturbance (1). Despite significant advances in understanding the pathological changes in PD, the etiology and the underlying mechanism responsible for the progressive nature of neurodegeneration remain poorly understood. Furthermore, current therapies are limited to relieving PD symptoms and are largely ineffective in halting the process of neurodegeneration. We have reported that dextromethorphan (DM), a widely used anticough agent, protected DA neurons against inflammagen LPS in midbrain neuron-glia cultures (2) and neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-elicited neurotoxicity in vivo (3) via an anti-inflammatory effect by preventing the over-activation of microglia. Furthermore, we recently reported that 3-hydroxymorphinan (3-HM), a metabolite of DM, exerted a more potent neuroprotection than DM against LPS-induced DA neurotoxicity in primary midbrain mixed neuron-glia cultures (4). We attribute the higher potency of 3-HM to its additional neurotrophic effect provided by astroglia
Hydrolytic oxidation of organosilanes to the corresponding silanols can be performed highly efficiently with a catalyst system of [IrCl(C(8)H(12))](2) under essentially neutral and mild conditions, and various types of silanols are produced in good to excellent yields.
Since allenes are versatile building blocks both for organic synthesis [1] and in transition-metal-promoted carbon±carbon bond-forming reactions, [2] development of practical methods for their preparation is of great interest. Allene moieties can be prepared by alkylation of allenylmethyl halides with an appropriate carbanionic species, [1e] by S N 2'-type selective displacement of propargyl alcohol derivatives with organocopper reagents, [1e, 3] and by intramolecular regio-and stereoselective reduction of alkynes. [4] The synthesis of allenes by metal-catalyzed cross-coupling reactions is an alternative method; [5] however, some disadvantages are the inconvenient preparation of the reagents, limited substrate scope, and incompatibility of sensitive groups to the reaction conditions. [6] Recently, several reports have described the synthesis of allenes with transition metal complexes. [5] Despite this recent progress a method for the highly efficient and catalytic synthesis of substituted allenes is still needed. We have realized this goal (Scheme 1) as part of our continuing studies directed toward the development of efficient indium-mediated reactions. [7] , [8] The catalytic activity of several palladium complexes was initially examined in the reaction of 1-iodonaphthalene with allenylindium. The best results were obtained with 4 mol % [Pd(PPh 3 ) 4 ] in the presence of 3 equivalents of LiI in DMF at 100 8C under a nitrogen atmosphere (see Experimental Section), and 1-allenylnaphthalene was produced in quantitative yield (98 %) with complete regioselectivity (Table 1, entry 1). The allenylindium reagent generated in situ from the reaction of 1 equivalent of indium with 1.5 equivalents of propargyl bromide gave the best results as a coupling partner. [9] To demonstrate the efficiency and scope of the present method, we applied this catalytic system to a variety of propargyl halides and organic electrophiles. For the propargyl halides as coupling partners, the presence of various alkyl substituents at the a and g positions had little effect on either the reaction rate or the product yield (Table 1). Under the optimized conditions, treatment of iodobenzene with 3bromo-1-phenyl-1-butyne and indium gave selectively trisubstituted allene 2 in 80 % yield (entry 2). Varying the electron demand of the substituents on the arene did not diminish the efficiency and selectivity (entries 3, 7±9). It is noteworthy that protection of an oxo group and a hydroxy group on substrates is not necessary, as demonstrated by the reactions of 4iodoacetophenone (entry 5) and 3-iodophenol (entry 6), respectively. Hetero substituents turned out to be compatible with the reaction conditions (entry 10). The method worked equally well with vinyl halides (entries 11 and 12) and imidoyl bromide (entry 13). Treatment of iodophenylacetylene with allenylindium produced 3-methyl-1-phenyl-3,4-pentadien-1yne (14) in 91 % yield (entry 14). In the case of vinyl triflate, the desired product 15 was obtained in 90 % yield (entry 15). Surprisingly...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.