The Protective and Reparative Role of Colony-Stimulating Factors in the Brain with Cerebral Ischemia/Reperfusion Injury

Abstract

Stroke is a debilitating disease and has the ability to culminate in devastating clinical outcomes. Ischemic stroke followed by reperfusion entrains cerebral ischemia / reperfusion (I/R) injury, which is a complex pathological process and is associated with serious clinical manifestations. Therefore, the development of a robust and effective post-stroke therapy is crucial. Granulocyte colony stimulating factor (GCSF) and erythropoietin (EPO), originally discovered as hematopoietic growth factors, are versatile and have transcended beyond their traditional role of orchestrating the proliferation, differentiation and survival of hematopoietic progenitors to one that fosters brain protection/ neuroregeneration. The clinical indication regarding GCSF and EPO as an auspicious therapeutic strategy is conferred in a plethora of illnesses, including anemia and neutropenia. EPO and GCSF alleviate cerebral I/R injury through a multitude of mechanisms, involving anti-apoptotic, anti-inflammatory, antioxidant, neurogenic and angiogenic effects. Despite bolstering evidence from preclinical studies, the multiple brain protective modalities of GCSF and EPO failed to translate in clinical trials and thereby raises several questions. The present review comprehensively compiles and discusses key findings from in vitro, in vivo and clinical data pertaining to the administration of EPO, GCSF, and other drugs which alter levels of colony stimulating factor (CSF) in the brain following cerebral I/R injury and elaborates on the contributing factors which led to the lost in translation of CSFs from bench to bedside. Any controversial findings are discussed to enable a clear overview of the role of EPO and GCSF as robust and effective candidates for post-stroke therapy.

Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial

“…In male mice with acute myeloid leukemia administered chemotherapeutic agents, impaired spermatogenesis and fertility were restored by G-CSF administration (21). In other experiments, G-CSF administration counteracted apoptosis (22,23,24), in ammatory states, (3,21,24), impaired vascularity (24,25), growth failure (24,26), and oxidative stress (3,24). Such restoration of a physiologic state might suggest mechanisms applicable to enhancement of preantral follicular growth in our patients with poor ovarian reserve.…”

“…Clinical safety and tolerance of G-CSF treatment have been established in healthy bone marrow donors treated for 3 to 5 days (26), patients with severe chronic neutropenia treated daily or on alternate days for up to 12 years (32), and patients undergoing ischemic stroke treatment involving G-CSF (24). In healthy bone marrow donors and patients with repeated implantation failure, unexplained repeated miscarriage, chemotherapy, or severe chronic neutropenia, administration of G-CSF during pregnancy (daily to every 3 days for 1 to 3 trimesters) has shown absence of major maternal or fetal/neonatal adverse effects, including teratogenicity (14-16, 26, 32, 33).…”

Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial

“…In male mice with acute myeloid leukemia administered chemotherapeutic agents, impaired spermatogenesis and fertility were restored by G-CSF administration [ 21 ]. In other experiments, G-CSF administration counteracted apoptosis [ 22 – 24 ], inflammatory states, [ 3 , 21 , 24 ], impaired vascularity [ 24 , 25 ], growth failure [ 24 , 26 ], and oxidative stress [ 3 , 24 ]. Such restoration of a physiologic state might suggest mechanisms applicable to enhancement of preantral follicular growth in our patients with poor ovarian reserve.…”

“…Clinical safety and tolerance of G-CSF treatment have been established in healthy bone marrow donors treated for 3 to 5 days [ 26 ], patients with severe chronic neutropenia treated daily or on alternate days for up to 12 years [ 32 ], and patients undergoing ischemic stroke treatment involving G-CSF [ 24 ]. In healthy bone marrow donors and patients with repeated implantation failure, unexplained repeated miscarriage, chemotherapy, or severe chronic neutropenia, administration of G-CSF during pregnancy (daily to every 3 days for 1 to 3 trimesters) has shown absence of major maternal or fetal/neonatal adverse effects, including teratogenicity [ 14 – 16 , 26 , 32 , 33 ].…”

Cerebral ischemia reperfusion injury: from public health perspectives to mechanisms

“…There are some good reviews which have comprehensively analysed different mechanisms which play a critical role in the pathogenesis of cerebral ischemia/ reperfusion injury [3,26,28,29,31,37,46]. In this review, we have summarized pioneering research works which greatly enhanced our understanding about underlying causes of cerebral ischemia/reperfusion injury.…”