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Spermine is neuroprotective against anoxia and N-methyl-D-aspartate in hippocampal slices
P A Ferchmin1, D Pérez, M Biello
1Center for Molecular and Behavioral Neuroscience, Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamon, USA. ferchmin@coqui.net
Abstract:
Polyamines were implicated as either neurotoxic or neuroprotective in several models of stroke. Spermine augments the excitotoxicity mediated by the N-methyl-D-aspartate (NMDA) receptor because this receptor is activated at micromolar spermine concentrations. However, at higher concentrations, spermine could be neuroprotective because it blocks the NMDA receptor and voltage-activated Ca(2+) channels. In this work, acute hippocampal slices were exposed to 1 mM spermine and either 10 min of anoxia or 0.5 mM NMDA. The percent recovery of population spikes was the measure of neuroprotection. One millimolar spermine was robustly neuroprotective; however, 0.1 mM spermine and 1 mM putrescine were not. The neuroprotective concentration of spermine was higher than the physiological concentration of free spermine. However, during an excitotoxic episode, extracellular Ca(2+) is decreased, enabling the inhibitory activity of lower spermine concentration. In addition, several noxious stimuli trigger the release of intracellular spermine and could raise local levels of spermine. Therefore, it is possible that spermine has a neuroprotective role in vivo.
Insights
Spermine demonstrates neuroprotective effects against stroke-related brain damage by blocking N-methyl-D-aspartate receptors. This protective role is evident at higher concentrations, suggesting a potential therapeutic application in vivo.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Polyamines, including spermine, have shown dual roles as neurotoxic or neuroprotective agents in stroke models.
- Spermine's interaction with N-methyl-D-aspartate (NMDA) receptors is concentration-dependent, augmenting excitotoxicity at micromolar levels but potentially offering protection at higher concentrations by blocking NMDA receptors and calcium channels.
Purpose of the Study:
- To investigate the neuroprotective potential of spermine in an in vitro model of stroke.
- To determine the concentration-dependent effects of spermine on neuronal survival following excitotoxic injury.
Main Methods:
- Acute hippocampal slices were subjected to anoxia or NMDA exposure.
- Treatment with varying concentrations of spermine (1 mM and 0.1 mM) and putrescine (1 mM).
- Neuroprotection was quantified by measuring the percent recovery of population spikes.
Main Results:
- 1 mM spermine exhibited robust neuroprotective effects against both anoxic and NMDA-induced injury.
- Lower concentrations (0.1 mM spermine) and putrescine (1 mM) did not show significant neuroprotection.
- The effective neuroprotective concentration of spermine exceeds typical physiological levels, but may be relevant during excitotoxic events due to altered extracellular calcium and spermine release.
Conclusions:
- Spermine possesses significant neuroprotective properties at millimolar concentrations in acute hippocampal slices.
- The study suggests a potential in vivo neuroprotective role for spermine, particularly under conditions of excitotoxicity where local concentrations may increase.