L‐Arginyl‐3,4‐Spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission

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Abstract
Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX‐3.3 toxin from which L‐Arginyl‐3,4‐Spermidine (L‐Arg‐3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail. In an in vitro ischaemia model, L‐Arg‐3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L‐Arg‐3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia. L‐Arg‐3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 μM L‐Arg‐3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices. L‐Arg‐3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly. Furthermore, L‐Arg‐3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side‐effects. Taken together, these results demonstrate that L‐Arg‐3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases. British Journal of Pharmacology (2002) 137, 1255–1268. doi:10.1038/sj.bjp.0704986