title: Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment.
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 P2Y2proposed 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.
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain. dreigada@sescam.jccm.es.
authors.forename: David
authors.identifier: 0000-0001-9041-0705
authors.initials: D
authors.lastname: Reigada
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Navarro-Ruiz
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Marcos Javier
authors.initials: MJ
authors.lastname: Caballero-López
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Del Águila
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Muñoz-Galdeano
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Maza
authors.affiliation: Molecular Neuroprotection Group, Experimental Neurology Unit, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Díaz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015226:Dinucleoside Phosphates / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D015226:Dinucleoside Phosphates; D018696:Neuroprotective Agents; C020733:diadenosine tetraphosphate; D002118:Calcium
keywords: Apoptosis; Diadenosine; Excitotoxicity; Intracellular calcium; Mouse model; Neuro-2a; Neuroprotection; Secondary injury; Spinal cord injury; Tissue damage