Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice

Mehrjerdi, Fatemeh Zare; Aboutaleb, Nahid; Habibey, Rouhollah; Ajami, Marjan; Soleimani, Mansoureh; Arabian, Maedeh; Niknazar, Somayeh; Davoodi, Sayed Hossein; Pazoki‐Toroudi, Hamidreza

doi:10.1016/j.brainres.2013.06.018

Cited by 46 publications

(36 citation statements)

References 27 publications

(31 reference statements)

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“…Emerging clinical trials have corroborated the previous research, suggesting that remote preconditioning may indeed protect the heart [9][10][11]. In addition, recent findings in experimental animal models and clinical studies suggest that remote ischemic preconditioning may also be beneficial to the brain without exacerbating intracerebral hemorrhage [12][13][14][15][16][17][18][19].…”

Section: Introductionsupporting

confidence: 54%

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

et al. 2015

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Symptomatic intracranial arterial stenosis (SIAS) is very common in octo-and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo-and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo-and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n=30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n=28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p<0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p<0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo-and nonagenarians with SIAS. A multicenter trial is ongoing.Clinical Trial Registration: www.clinicaltrials.gov, unique identifier: NCT01570231.

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Section: Introductionsupporting

confidence: 54%

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

et al. 2015

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“…In the brain, the mTOR pathway regulates synaptic plasticity, neuronal transmission, axon outgrowth, neuronal size, and spine morphology, thus loss of homeostasis of mTOR pathway is involved in a variety of neurologic diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease 7, 8, 9, 10. Numerous reports have demonstrated that mTOR pathway is involved in brain ischemia–reperfusion induced injury 11, 12, 13, 14, 15, 16. However, whether upregulating or downregulating mTOR pathway has a protective effect on neurons in ischemia–reperfusion injury remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWhether activation or inhibition of the mTOR pathway is beneficial to ischemic injury remains controversial. It may result from the different reaction of ischemic penumbra and core to modulation of mTOR pathway after cerebral ischemia–reperfusion injury in rats.MethodsLonga's middle cerebral artery occlusion (MCAO) method was conducted to induce the focal cerebral ischemia–reperfusion. Western blot analysis was used to examine the protein expression involving mTOR pathway, apoptosis, and autophagy‐related proteins. TTC staining and Fluoro‐Jade B staining was conducted to detect the infarct volume and cell apoptosis, respectively. Neurological function was measured by modified neurological severity score and left‐biased swing.Results mTOR signaling pathway was activated in ischemic penumbra and decreased in ischemic core after ischemia and ischemia–reperfusion. Ischemia–reperfusion injury induced the increase in cleaved caspase 9 and caspase 3 both in ischemic penumbra and in ischemic core, whereas the expression of phosphorylated ULK1, Beclin 1 and LC3‐II was decreased. Rapamycin pre or postadministration inhibited the overactivation of mTOR pathway in ischemic penumbra. Ameliorated neurological function and reduced infarct volume were observed after pre or postrapamycin treatment. Rapamycin markedly decreased the number of FJB‐positive cells and the expression of cleaved caspase‐3 and cleaved caspase‐9 proteins as well as increased the activation of autophagy reflected by ULK1, Beclin‐1 and LC3.Interpretation mTOR signaling pathway was activated in ischemic penumbra after cerebral ischemia–reperfusion injury in rats. mTOR inhibitor rapamycin significantly decreased the mTOR activation and infarct volume and subsequently improved neurological function. These results may relate to inhibition of neuron apoptosis and activation of autophagy.

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“…It should be mentioned that, in that study, mammalian target of rapamycin (MTOR) was investigated as the involved mechanism (Zare Mehrjerdi et al 2013). In this study, we reported that remote renal preconditioning can protect the hippocampus against ischemia reperfusion injuries through several mechanisms: activating KATP channels and increasing antioxidative enzyme.…”

Section: Introductionmentioning

confidence: 93%

“…Body temperature was monitored with the rectal thermometer throughout the surgery and kept at 36.5±0.5°C by a heating pad. After shaving the left area of the abdomen, the left renal pedicle including the renal artery and vein was isolated from surrounding tissue and was clamped by a non-traumatic clamp for 3 cycles of 5 min ischemic and 5 min reperfusion, then the incision was sutured (Zare Mehrjerdi et al 2013).…”

Section: Remote Renal Preconditioningmentioning

confidence: 99%

The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels

et al. 2015

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Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P< 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC.

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Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice

Cited by 46 publications

References 27 publications

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels

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