Alpha-synuclein （a-syn） deposition in Lewy bodies （LB） is one of the main neuropathological hallmarks of Parkinson＇s disease （PD）. LB accumulation is considered a causative factor of PD, which suggests that str...Alpha-synuclein （a-syn） deposition in Lewy bodies （LB） is one of the main neuropathological hallmarks of Parkinson＇s disease （PD）. LB accumulation is considered a causative factor of PD, which suggests that strategies aimed at reducing a-syn levels could be relevant for its treatment. In the present study, we developed novel nanocarriers suitable for systemic delivery of small interfering ribonucleic acid （siRNA） that were specifically designed to reduce neuronal α-syn by RNA interference. Anionic liposomes loaded with an siRNA-protamine complex for α-syn gene silencing and decorated with a rabies virus glycoprotein （RVG）-derived peptide as a targeting agent were prepared. The nanoparticles were characterized for their ability to load, protect, and deliver the functional siRNA to mouse primary hippocampal and cortical neurons as well as their efficiency to induce gene silencing in these cells. Moreover, the nanocarriers were evaluated for their stability in serum. The RVG-decorated liposomes displayed suitable characteristics for future in vivo applications and successfully induced α-syn gene silencing in primary neurons without altering cell viability. Collectively, our results indicate that RVG-decorated liposomes may be an ideal tool for further studies aimed at achieving efficient in vivo α-syn gene silencing in mouse models of PD.展开更多
The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (1...The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (12 days after plating) to 0.5 mmol/L glutamate for 30 min resulted in significant cell damage. Pretreatment with bis(7) tacrine (0.03 1.0 μmol/L) reduced the glutamate induced neurotoxicity in a concentration dependent manner and the maximal response was seen at 1 μmol/L with approximately 30% protection. A receptor binding assay showed that bis(7) tacrine can completely displace MK 801 binding to rat cortical membrane with an IC 50 of 0.57 μmol/L. These findings suggest that bis(7) tacrine can directly interact with N methyl D aspartate receptor channel complex, which may contribute to the inhibitor's protective effects against glutamate induced excitotoxicity. Thus, it is possible that anti glutamate/anti AChE synergism is responsible for potentially better Alzheimer's therapy of bis(7) tacrine relative to tacrine.展开更多
文摘Alpha-synuclein （a-syn） deposition in Lewy bodies （LB） is one of the main neuropathological hallmarks of Parkinson＇s disease （PD）. LB accumulation is considered a causative factor of PD, which suggests that strategies aimed at reducing a-syn levels could be relevant for its treatment. In the present study, we developed novel nanocarriers suitable for systemic delivery of small interfering ribonucleic acid （siRNA） that were specifically designed to reduce neuronal α-syn by RNA interference. Anionic liposomes loaded with an siRNA-protamine complex for α-syn gene silencing and decorated with a rabies virus glycoprotein （RVG）-derived peptide as a targeting agent were prepared. The nanoparticles were characterized for their ability to load, protect, and deliver the functional siRNA to mouse primary hippocampal and cortical neurons as well as their efficiency to induce gene silencing in these cells. Moreover, the nanocarriers were evaluated for their stability in serum. The RVG-decorated liposomes displayed suitable characteristics for future in vivo applications and successfully induced α-syn gene silencing in primary neurons without altering cell viability. Collectively, our results indicate that RVG-decorated liposomes may be an ideal tool for further studies aimed at achieving efficient in vivo α-syn gene silencing in mouse models of PD.
文摘The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (12 days after plating) to 0.5 mmol/L glutamate for 30 min resulted in significant cell damage. Pretreatment with bis(7) tacrine (0.03 1.0 μmol/L) reduced the glutamate induced neurotoxicity in a concentration dependent manner and the maximal response was seen at 1 μmol/L with approximately 30% protection. A receptor binding assay showed that bis(7) tacrine can completely displace MK 801 binding to rat cortical membrane with an IC 50 of 0.57 μmol/L. These findings suggest that bis(7) tacrine can directly interact with N methyl D aspartate receptor channel complex, which may contribute to the inhibitor's protective effects against glutamate induced excitotoxicity. Thus, it is possible that anti glutamate/anti AChE synergism is responsible for potentially better Alzheimer's therapy of bis(7) tacrine relative to tacrine.
