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Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment

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Abstract

Reducing cell death during the secondary injury is a major priority in the development of a cure for traumatic spinal cord injury (SCI). One of the earliest processes that follow SCI is the excitotoxicity resulting from the massive release of excitotoxicity mediators, including ATP, which induce an excessive and/or prolonged activation of their receptors and a deregulation of the calcium homeostasis. Diadenosine tetraphosphate (Ap4A) is an endogenous purinergic agonist, present in both extracellular and intracellular fluids, with promising cytoprotective effects in different diseases including neurodegenerative processes. In a search for efficient neuroprotective strategies for SCI, we have tested the capability of Ap4A to reduce the excitotoxic death mediated by the ATP-induced deregulation of calcium homeostasis and its consequences on tissue preservation and functional recovery in a mouse model of moderate contusive SCI. Our analyses with the murine neural cell line Neuro2a demonstrate that treatment with Ap4A reduces ATP-dependent excitotoxic death by both lowering the intracellular calcium response and decreasing the expression of specific purinergic receptors. Follow-up analyses in a mouse model of contusive SCI showed that acute administration of Ap4A following SCI reduces tissue damage and improves motor function recovery. These results suggest that Ap4A cytoprotection results from a decrease of the purinergic tone preventing the effects of a massive release of ATP after SCI, probably together with a direct induction of anti-apoptotic and pro-survival pathways via activation of P2Y2 proposed in previous studies. In conclusion, Ap4A may be a good candidate for an SCI therapy, particularly to reduce excitotoxicity in combination with other modulators and/or inhibitors of the excitotoxic process that are being tested.

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Acknowledgments

We would like to thank Dr. Claire H. Mitchell and Dr. Jesús Pintor for their helpful comments and their kind criticism in the preparation of this manuscript. This work was supported by Fundación para la Investigación Sanitaria de Castilla la Mancha (FISCAM). PI-2010/19. We thank the technical and logistic support to the Fundación del Hospital Nacional de Parapléjicos para la Investigación y la Integración (FUHNPAIIN) and the microscopy and cytometry facilities of the Experimental Neurology Unit, Hospital Nacional de Parapléjicos, Toledo, Spain.

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  1. Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain

    David Reigada, Rosa María Navarro-Ruiz, Marcos Javier Caballero-López, Ángela Del Águila, Teresa Muñoz-Galdeano, Rodrigo M. Maza & Manuel Nieto-Díaz

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  1. David Reigada
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  2. Rosa María Navarro-Ruiz
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  3. Marcos Javier Caballero-López
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  4. Ángela Del Águila
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  5. Teresa Muñoz-Galdeano
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  7. Manuel Nieto-Díaz
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Correspondence to David Reigada.

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Reigada, D., Navarro-Ruiz, R.M., Caballero-López, M.J. et al. Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment. Purinergic Signalling 13, 75–87 (2017). https://doi.org/10.1007/s11302-016-9541-4

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  • DOI: https://doi.org/10.1007/s11302-016-9541-4

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