Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury

Reigada, David; Nieto‐Díaz, Manuel; Navarro-Ruíz, Rosa; Caballero-López, Marcos; Águila, Ángela del; Muñoz‐Galdeano, Teresa; Maza, Rodrigo M.

doi:10.1016/j.neuroscience.2015.05.036

Cited by 12 publications

(49 citation statements)

References 70 publications

(121 reference statements)

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“…In agreement, we observed that intraperitoneal administration of Ap 4 A after contusion in a mouse model of SCI induces improved inter-limb coordination earlier and to a larger extent than vehicle-treated mice. Coordination is a major milestone rarely reached by untreated C57BL/6J after a moderate SCI [74,98] that precedes a more extensive recovery [99], depending on the conservation of local networks or propriospinal interneurons (PNs) that build up the central patterns generators (CPGs) and rhythmic locomotive movements [100,101]. The conservation of these circuits is reflected in the increase of spared white matter in Ap 4 A-treated mice, especially in sections caudal to the injury place.…”

Section: Discussionmentioning

confidence: 99%

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

Reigada

Navarro-Ruíz

Caballero-López

et al. 2016

Purinergic Signalling

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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 (Ap 4 A) 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 Ap 4 A 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 Ap 4 A 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 Ap 4 A following SCI reduces tissue damage and improves motor function recovery. These results suggest that Ap 4 A 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 P2Y 2 proposed in previous studies. In conclusion, Ap 4 A 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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Section: Discussionmentioning

confidence: 99%

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

Reigada

Navarro-Ruíz

Caballero-López

et al. 2016

Purinergic Signalling

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“…For mice models, 12-15 weeks old individuals (20 grams) were anesthetized through isoflurane (Forane, Baxter Health Care Corporation) inhalation (2% in oxygen for induction and 1.5% during surgery) and by subcutaneous administration of buprenorfine as analgesic. SCI surgery followed the methodology described in Reigada et al [14].…”

Section: Sci Proceduresmentioning

confidence: 99%

“…Staining of myelinated tissue in spinal cord sections by eriochrome cyanine (EC) followed by the Cavalieri's stereological estimation for white matter preservation is an easy and broadly employed technique to measure neurodegeneration. In previous works we have employed this methodology to estimate tissue preservation in different animal models, SCI severities and neuroprotective treatments [12][13][14] under the assumption that the resulting estimation of the tissular damage highly correlates with the physiological deficits induced by SCI and the efficacy of any therapeutical strategy.…”

Section: Introductionmentioning

confidence: 99%

Stereological Evaluation of Tissue Preservation After Neuroprotective Treatments for Traumatic Spinal Cord Injury

Reigada

Soto

González-Rodríguez

et al. 2022

Preprint

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Spinal cord injury (SCI) is a major cause of permanent disability and its causes and pathophysiological effects are very variables between patients. The assessment of tissue damage extent and neurodegeneration degree correlated with the functional evaluation are the most accepted tools to diagnose and prognose the trauma severity. Animal models of SCI have been used for treatment development and in the present work we evaluate the potency of stereological tools to estimate damage degree for a diagnostic of neural degeneration and locomotor and sensorial disability after SCI and the efficacy of different types of therapeutic strategies.

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“…After disinfection, 1.0 cm scalp coronal incision was made and a 1.0 mm-diameter hole was drilled about 4.5 mm from the anterior fontanel. Under the stereotactic guidance, fresh autologous non-heparinized arterial blood (0.35 mL) from the femoral artery was injected aseptically into the hole (prechiasmatic cistern) in 20 s with a syringe pump in the SAH group, and allowed the syringe pump to remain for more than 2 min, preventing blood flowing backwards and the leakage of cerebrospinal fluid (Reigada et al 2015). Rats in Sham group underwent the same procedure; however, the rats in the sham group were injected with 0.35 ml saline.…”

Section: Animal Model and Treatmentmentioning

confidence: 99%

“…Higher level of Omi/HtrA2 distinctly promotes neuronal apoptosis in cerebral ischemia/reperfusion (Althaus et al 2007), hippocampal neurons injury (Rami et al 2010), and neurodegenerative diseases (Li et al 2010), etc. Pre-treatment with UCF-101, a selective inhibitor of Omi/HtrA2 protease activity significantly reduces neuronal cell apoptosis and attenuates sepsis-induced cognitive dysfunction (Cilenti et al 2003;Hu et al 2013), protects against cerebral ischemia/reperfusion injury (Su et al 2009), and traumatic spinal cord injury-induced locomotor impairments (Reigada et al 2015). Therefore, the regulation of Omi/ HtrA2 activity possibly facilitates the repair of neurological deficit and early brain injury via anti-apoptosis effect.…”

Section: Introductionmentioning

confidence: 99%

Omi inhibition ameliorates neuron apoptosis and neurological deficit after subarachnoid hemorrhage in rats

Yang

Dong

et al. 2021

Genes Genom

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Background Subarachnoid hemorrhage (SAH) is a severe neurological emergency, resulting in cognitive impairments and threatening human's health. Currently, SAH has no effective treatment. It is urgent to search for an effective therapy for SAH. Objective To explore the expression of Omi protein after subarachnoid hemorrhage in rats. Methods SAH rat model was established by injecting blood into the prechiasmatic cistern. Neurological deficit was assessed by detecting neurological deficit scores and brain tissue water contents. Apoptotic cells were evaluated by TUNEL staining and IHC staining. Omi and Cleaved caspase 3 expressions in nerve cells were determined by double staining using IF. Apoptosis-related proteins were measured by Western blotting assay. Results SAH rat model was successfully established, showing more apoptotic cells and high neurological deficit scores in SAH rat. In SAH rat model, Omi expression in nerve cells was elevated and the upregulation of Omi mainly occurred in cytoplasm, accompanied by the degradation of XIAP and the increased cleaved caspase 3/9 and cleaved PARP. Once treated with UCF-101, a specific inhibitor of Omi, the increased cell apoptosis, left/right brain moisture contents and neurological deficits were notably reversed in SAH rat brain. Of note, SAH-induced the increases of apoptosis-related protein in nerve cells were also rescued by the administration of UCF-101. Conclusions UCF-101-mediated Omi inhibition decreased the degradation of XIAP and subsequently inhibited the activation of apoptosis-related proteins, decreased nerve cell apoptosis, leading to the improvement on early brain injury in SAH rat. UCF-101-based Omi inhibition may be used to treat SAH with great potential application.

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Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury

Cited by 12 publications

References 70 publications

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

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

Stereological Evaluation of Tissue Preservation After Neuroprotective Treatments for Traumatic Spinal Cord Injury

Omi inhibition ameliorates neuron apoptosis and neurological deficit after subarachnoid hemorrhage in rats

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