Ginkgo biloba Extract Prevents Female Mice from Ischemic Brain Damage and the Mechanism Is Independent of the HO1/Wnt Pathway

Abstract

It is well known that gender differences exist in experimental or clinical stroke with respect to brain damage and loss of functional outcome. We have previously reported neuroprotective properties of Ginkgo biloba/EGb 761® (EGb 761) in transient and permanent mouse models of brain ischemia using male mice, and the mechanism of action was attributed to the upregulation of the hemeoxygenase 1 (HO1)/Wnt pathway. Here, we sought to investigate whether EGb 761’s protective effect in ovariectomized female mice following stroke is also mediated by the HO1/Wnt pathway. Female mice were ovariectomized (OVX) to remove the protective effect of estrogen and were treated with EGb 761 for 7 days prior to inducing permanent middle cerebral artery occlusion (pMCAO) and allowed to survive for additional 7 days. At day 8, animals were sacrificed, and brains were harvested for infarct volume analysis, western blots, and immunohistochemistry. The OVX female mice treated with EGb 761 showed significantly lower infarct size as compared to that of Veh/OVX animals. EGb 761 treatment in female mice inhibited apoptosis by preventing caspase-3 cleavage and blocking the extrinsic apoptotic pathway. EGb 761 pretreatment significantly enhanced neurogenesis in OVX mice as compared to the Veh/OVX group and significantly upregulated androgen receptor expression with no changes in HO1/Wnt signaling. These results suggest that EGb 761 prevented brain damage in OVX female mice by improving grip strength and neurological deficits, and the mechanism of action is not through HO1/Wnt but via blocking the extrinsic apoptotic pathway.

Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury

“…Following ICH induction, a large number of free radicals were released, and ROS led to membrane lipid peroxidation and protein and DNA oxidative damage [ 51 – 53 ]. HO-1 protected cells and tissues during oxidative stress as an important member of antioxidant [ 54 – 56 ]. NQO1 used NADH or NADPH as electron donors to catalyze the reduction of chinone compounds, thereby avoiding the formation of unstable semiquinone compounds [ 56 , 57 ].…”

Tnfrsf12a-Mediated Atherosclerosis Signaling and Inflammatory Response as a Common Protection Mechanism of Shuxuening Injection Against Both Myocardial and Cerebral Ischemia-Reperfusion Injuries

“…Inhibition of catecholamine biosynthesis has been shown to reduce acute ischemic stroke ( Welch et al, 1977 ) and this may provide a new light for SXNI to treat CIRI. Protection of brain from injury and related symptoms are the most documented beneficial effects by EGB ( Calapai et al, 2000 ; DeKosky et al, 2008 ; Oliveira et al, 2009 ; Shi et al, 2010 ; Rocher et al, 2011 ; Abdel-Wahab and Abd El-Aziz, 2012 ; Tanaka et al, 2013 ; Tulsulkar and Shah, 2013 ; Nada et al, 2014 ; Belviranli and Okudan, 2015 ; Liu et al, 2015 ; Wu et al, 2015 ; Kim et al, 2016 ; Tulsulkar et al, 2016 ). G-protein coupled receptor (GPCR) are the most abundant receptor type in the central nervous system and are linked to platelet activation, BBB function and endothelial dysfunction ( Guerram et al, 2016 ), leading to another insight of SXNI for CIRI.…”

“…A recent search of PubMed with the keyword combinations of “Ginkgo biloba AND brain” or “Ginkgo biloba AND heart” yielded 579 or 145 reports, respectively. For brain-related diseases, EGB is reported to have a beneficial effect on acute cerebral infarction ( Wu et al, 2015 ), chronic cerebral hypoperfusion ( Kim et al, 2016 ), brain damage ( Tulsulkar et al, 2016 ), ischemic stroke ( Calapai et al, 2000 ; Nada et al, 2014 ), hippocampal neuronal loss ( Rocher et al, 2011 ; Tulsulkar and Shah, 2013 ), cognitive impairment ( Belviranli and Okudan, 2015 ), memory deficit ( Oliveira et al, 2009 ; Abdel-Wahab and Abd El-Aziz, 2012 ), dementia ( DeKosky et al, 2008 ), Parkinson’s disease ( Tanaka et al, 2013 ) and Alzheimer’s disease ( Shi et al, 2010 ; Liu et al, 2015 ), with its mechanisms of action such as resisting apoptosis, oxidative stress, inflammatory response, immune response and platelet activation ( Kleijnen and Knipschild, 1992 ; Smith and Luo, 2004 ; Chan et al, 2007 ; Diamond and Bailey, 2013 ; Mohanta et al, 2014 ). In addition, EGB also exerts protective effect on heart-related diseases, including cardiac injury ( Boghdady, 2013 ), arrhythmia ( Zhao et al, 2013 ), myocardial ischemia ( Wang Z. et al, 2016 ), myocardial infarction ( Liu A. H. et al, 2013 ; Liu et al, 2014 ) and doxorubicin-induced cardiotoxicity ( Naidu et al, 2002 ) mainly via antioxidant, anti-apoptotic, anti-inflammation, and anti-mitochondrial oxidative damage.…”

Upregulation of heme oxygenase‑1 protected against brain damage induced by transient cerebral ischemia‑reperfusion injury in rats

“…Gene transfer was used in the present study to investigate stroke by transducing genes into neurons ( 11 ). There are alternative approaches for expressing transgenes of interest in adult animals, and then investigating their effects on cerebral ischemia-reperfusion injury ( 11 ).…”