Granulocyte-colony stimulating factor protects against endoplasmic reticulum stress in an experimental model of stroke

Menzie-Suderam, Janet; Mohammad-Gharibani, Payam; Modi, Jigar; Ma, Z.; Tao, Rui; Prentice, Howard; Wu, Jang Yen

doi:10.1016/j.brainres.2017.12.022

Cited by 26 publications

(33 citation statements)

References 63 publications

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“…Phosphorylated Akt (P-Akt) is a well-established biomarker for cell protection [33], levels of P-Akt is increased as G-CSF binds to G-CSF receptor at cell membrane [23]. We found that P-Akt, a pro-survival biomarker, is increased towards normal levels by G-CSF treatment as shown in Fig.…”

Section: Resultsmentioning

confidence: 61%

“…1e). Although we did not quantify infarct volume in this study, the infarct representation is supported by several evidence that G-CSF significantly reduces infarct volume in cerebral ischemia on day 4 [23,36].…”

Section: Resultsmentioning

confidence: 63%

“…Downstream functions of the PERK, ATF6 and IRE1 pathways will upregulate UPR genes and ER-associated degradation (ERAD) genes that will reduce the unfolded proteins in the ER [22]. However, in sustained ER stress the proapoptotic transcription factor, C/EBP homologous protein (CHOP) [23] is activated resulting in apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…With only limited progress in development of stroke treatments, it is therefore essential to acquire valuable neuroprotective agents to effectively treat stroke. G-CSF controls the generation, proliferation, survival, and maturation of neutrophilic granulocytes and provokes their release from bone marrow to the peripheral blood [23,24]. G-CSF is an FDA approved hematopoietic growth factor and is currently employed in clinical practice to cure neutropenia caused by chemotherapy [25].…”

Section: Introductionmentioning

confidence: 99%

“…G-CSF is an FDA approved hematopoietic growth factor and is currently employed in clinical practice to cure neutropenia caused by chemotherapy [25]. G-CSF displays several important functions including anti-apoptotic activity, immunomodulatory action, stimulates neurogenesis, and angiogenic capabilities [23].…”

Section: Introductionmentioning

confidence: 99%

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Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Modi

Menzie-Suderam

et al. 2020

J Biomed Sci

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Background: The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress. Methods: Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 μg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting.Results: G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA. Conclusions: G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 63%