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

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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