Neuroprotective effect of epidermal growth factor plus growth hormone-releasing peptide-6 resembles hypothermia in experimental stroke

Subirós, Nelvys; Pérez-Saad, Héctor; Aldana, Lizet; Gibson, Claire L.; Borgnakke, Wenche S.; Garcia-del-Barco, D.

doi:10.1080/01616412.2016.1235249

Cited by 8 publications

(7 citation statements)

References 67 publications

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“…The hazard ratio indicates a 79% decreased risk of death in patients who received the combined therapy. The survival outcome of this study was consistent with the robust preclinical evidence obtained in animal models of acute focal and global brain ischemia ( 17 , 18 ). This suggests local and systemic cytoprotection induced by EGF+GHRP6 that eventually preserves organs and systems vulnerable to dysautonomies typical of stroke ( 58 – 60 ).…”

Section: Discussionsupporting

confidence: 86%

“…Later, EGF+GHRP6 combined therapy improved both clinical and pathological aspects as it reduced neurological symptoms and brain infarct volume, preserving neuronal density (17). Additionally, EGF+GHRP6 combined therapy achieved similar results in a preclinical context when compared to therapeutic hypothermia (18). Moreover, both active ingredients exhibited a high safety profile in preclinical and clinical trials (32,33).…”

Section: Introductionmentioning

confidence: 96%

“…Molecules that trigger cytoprotective effects can be considered candidates for combined therapies (8). Particularly, a combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) has demonstrated benefit in preclinical contexts by activating pleiotropic endogenous mechanisms of survival and brain protection (15)(16)(17)(18)(19). Both molecules cross the blood-brain barrier (20)(21)(22)(23), and their receptors are widely distributed in brain tissues (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Hernández-Bernal,

Estenoz-García,

Gutiérrez-Ronquillo

et al. 2024

Front. Neurol.

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ObjectiveThis study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.MethodsA multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.ResultsThe study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.ConclusionEGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.Clinical Trial RegistrationRPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Hernández-Bernal,

Estenoz-García,

Gutiérrez-Ronquillo

et al. 2024

Front. Neurol.

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“…Other neuroprotective agents such as corticosteroids [ 210 , 211 ], barbiturates [ 212 ], ketamine [ 213 ], citicoline [ 214 , 215 ], growth factors [ 216 – 219 ], minocycline [ 220 , 221 ] and mannitol [ 222 ] with their mechanisms of action are summarized in Table 2 .…”

Section: Neuroprotective Agentsmentioning

confidence: 99%

Neuroprotective Agents in the Intensive Care Unit

et al. 2018

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“…Stroke is one of the most prominent causes of death and disability in adults; however, there are few treatments associated with this condition [ 1 ]. Focal cerebral ischemia represents ischemic stroke [ 2 ], and reperfusion injury represents a common complication of recanalization therapies following AIS [ 3 ]. Mild hypothermia (MH) is a promising neuroprotective therapy for stroke management.…”

Section: Introductionmentioning

confidence: 99%

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

Zhou

Wang

et al. 2017

Oncotarget

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We assessed neurological outcomes, infarct volume, and the expression of nestin and caspase-3 in the hippocampal dentate gyrus following middle cerebral artery occlusion (MCAO) followed by reperfusion, with mild hypothermia (MH) treatment at the onset of ischemia in a MCAO rat model. Reperfusion began 2 hours after the MCAO model was set-up. MH treatment began at the onset of ischemia and was maintained for 4 hours. We evaluated neurological deficit score, brain infarct volumes, along with the immunohistochemical staining of nestin and caspase-3 in the sub-granular zone of the injured hemisphere on the 1st, 3rd, 7th, and 14th day after the onset of ischemia. Correlations between the number of nestin-positive (nestin+) cells, caspase-3-positive (caspase-3+) cells with infarct volume, as well as neurological deficit scores, were evaluated by linear regression. MH significantly promoted survival, reduced mortality, improved neurological deficit score, reduced brain infarct volume, increased the number of neural stem/progenitor cells and inhibited neuronal apoptosis in the sub-granular zone of the injured hemisphere. The number of nestin+ cells correlated with neurological deficit score in the normothermic group, and with infarct volume in the hypothermia group except for the first day after the onset of ischemia. The number of caspase-3+ cells correlated with the neurological deficit score but not infarct volume. The neuroprotective effects of MH may be mediated by modulating neural stem/progenitor cells and neuronal apoptotic cells in the sub-granular zone of the injured hemisphere during cerebral ischemia/reperfusion injury.

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Neuroprotective effect of epidermal growth factor plus growth hormone-releasing peptide-6 resembles hypothermia in experimental stroke

Abstract: With hypothermia being a good standard neuroprotectant reference, these results provide additional proof of principle for EGF and GHRP-6 co-administration as a potentially neuroprotective stroke therapy.

Cited by 8 publications

References 67 publications

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Neuroprotective Agents in the Intensive Care Unit

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

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