PAF antagonism to prevent epileptogenesis

Musto AE, Rosencrans RF, Walker CP, Bhattacharjee S, Raulji CM, Belayev L,

Fang Z, Gordon WC, Bazan NG. Dysfunctional epileptic neuronal circuits and

dysmorphic dendritic spines are mitigated by platelet-activating factor receptor

antagonism. Sci Rep. 2016 Jul 22;6:30298.

Abstract

Temporal lobe epilepsy or limbic epilepsy lacks effective therapies due to a void in understanding the cellular and molecular mechanisms that set in motion aberrant neuronal network formations during the course of limbic epileptogenesis (LE). Here we show in in vivo rodent models of LE that the phospholipid mediator platelet-activating factor (PAF) increases in LE and that PAF receptor (PAF-r) ablation mitigates its progression. Synthetic PAF-r antagonists, when administered intraperitoneally in LE, re-establish hippocampal dendritic spine density and prevent formation of dysmorphic dendritic spines. Concomitantly, hippocampal interictal spikes, aberrant oscillations, and neuronal hyper-excitability, evaluated 15-16 weeks after LE using multi-array silicon probe electrodes implanted in the dorsal hippocampus, are reduced in PAF-r antagonist-treated mice. We suggest that over-activation of PAF-r signaling induces aberrant neuronal plasticity in LE and leads to chronic dysfunctional neuronal circuitry that mediates epilepsy.

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From the article:

Conclusion

We conclude that an increase in PAF activates PAF-r in the hippocampus during epileptogenesis, thus mediating neuronal network hyper-excitability and seizure susceptibility. By blocking PAF-r and using the PAF-r antagonist during epileptogenesis, aberrant connectivity in the hippocampus was limited and, as a consequence, onset of epilepsy was reduced. We speculate that PAF-r activity could mediate aberrant connectivity in epileptogenesis.

Taken together, our observations suggest that the neuronal circuitry in the epileptic brain is enhanced by PAF-r over-activity during epileptogenesis. More experimental studies need to be conducted to elucidate the molecular and neurotransmission-related mechanisms involved in this process. Furthermore, understanding PAF antagonism and the potential therapeutic usefulness of PAF receptor antagonists is relevant to developing disease-modifying therapeutic interventions for patients at risk for epilepsy.

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