Development of therapeutics for ischemic brain damge by interrupting synaptic transmissions with the intraventricular infusion of antisense DNA

1.通过阻断易化传入防止海马神经元的缺血性损伤：损伤向海马投射通路的内侧隔可防止海马CA 1神经元的缺血性损伤，而损伤接受来自海马的传入通路的外侧隔不影响缺血性CA 1损伤。由于内侧隔-海马传入对海马回路的神经活动起易化系统的作用，因此损毁内侧隔对海马CA 1区缺血性损伤的保护作用提示，阻断内侧隔的易化传入可抑制缺血时海马回路过度兴奋的发生。导致海马CA 1神经元免于缺血性延迟细胞死亡。从目前的结果来看，很可能通过任何治疗方法干预海马的易化突触输入能够预防神经元的缺血性损伤。 ...更多信息 .脑室内注射突触素I反义DNA对缺血性海马损伤的恶化：我们研究了脑室内注射突触素I反义DNA是否能阻止海马CA 1区神经元缺血性细胞死亡的发生，突触素I在突触释放的调节系统中起作用。为了将反义DNA有效地导入脑组织，我们采用了具有细胞融合能力的HJV-脂质体作为寡核苷酸载体。缺血前4天侧脑室注射突触蛋白I反义DNA的大鼠，4血管阻断造成的前脑缺血20分钟，海马CA 1区神经元的损伤比缺血前未经任何治疗的大鼠更严重。从这种恶化的反义DNA对突触蛋白I在缺血性损伤的CA 1神经元，它已被认为是突触蛋白I的表达，它在抑制系统的突触释放发挥作用的阻断促进释放的兴奋性递质在缺血期间和之后，导致恶化的兴奋毒性细胞死亡的海马CA 1神经元。少

1. Prevention of ischemic damage of hippocampal neurons by interruption of facilitatory affrent :Lesion of the medial septum which projects pathways to the hippocampus prevents ischemic damage of hippocampal CA1 neurons, while the lesion of the lateral septum which receives afferent pathways from the hippocampus does not affect the ischemic CA1 damage. Since the medial septum-hippocampus afferents act as a facilitatory system to neural activity of hippocampal circuits, this protective effect of lesion of the medial septum on ischemic damage of hippocampal CA1 suggest that interruption of the facilitatory affarents from the medial septum may suppress occurrence of excessive excitation within the hippocamapl circuits during ischemia, resulting in a rescue of hippocampal CA1 neurons from ischemic delayd cell death. From the present result, it is quite likely that intervention in facilitatory synaptic inputs to hippocampus with any treatments is able to prevent ischemic damage of neurons.2 … More . Deterioration of ischemic hippocampal damage by intraventricular infusion of antisenseDNA against synapsin I :We have examined whether intraventricular administration of antisense DNA against synapsin I which functions in the regulation system of synaptic release prevents the occurrence of ischemic cell death of hippocampal CA1 neurons. To introduce antisense DNA efficiently into brain tissue, we used HJV-liposome as a vector of oligo nucleotides, which has a capability for cell fusion. In rats with intraventricular administration of antisense DNA against synapsin I 4 days prior to ischemia, 20 min of forebrain ischemia by 4-vessel occlusion caused severer damage of neurons in the hippocampal CA1 sector than that in ischemic rats without any prior treatment. From this deterioration by antisense DNA against synapsin I in ischemic damage of CA1 neurons, it has been suggested that the blockade of expression of synapsin I which plays a role in inhibitory system of synaptic release facilitates the release of excitatory transmitters during and after ischemia, leading to deterioration in the excitotoxic cell death of hippocampal CA1 neurons. Less