Neuroprotective Effect and Possible Mechanisms of Ginsenoside-Rd for Cerebral Ischemia/Reperfusion Damage in Experimental Animal: A Meta-Analysis and Systematic Review

Abstract

Ischemic stroke, the most common type of stroke, can lead to a long-term disability with the limitation of effective therapeutic approaches. Ginsenoside-Rd (G-Rd) has been found as a neuroprotective agent. In order to investigate and discuss the neuroprotective function and underlying mechanism of G-Rd in experimental animal models following cerebral ischemic/reperfusion (I/R) injury, PubMed, Embase, SinoMed, and China National Knowledge Infrastructure were searched from their inception dates to May 2022, with no language restriction. Studies that G-Rd was used to treat cerebral I/R damage in vivo were selected. A total of 18 articles were included in this paper, and it was showed that after cerebral I/R damage, G-Rd administration could significantly attenuate infarct volume (19 studies, SMD = -1.75 [-2.21 to - 1.30], P < 0.00001). Subgroup analysis concluded that G-Rd at the moderate doses of >10- <50 mg/kg reduced the infarct volume to the greatest extent, and increasing the dose beyond 50 mg/kg did not produce better results. The neuroprotective effect of G-Rd was not affected by other factors, such as the animal species, the order of administration, and the ischemia time. In comparison with the control group, G-Rd administration could improve neurological recovery (lower score means better recovery: 14 studies, SMD = -1.50 [-2.00 to - 1.00], P < 0.00001; higher score means better recovery: 8 studies, SMD = 1.57 [0.93 to 2.21], P < 0.00001). In addition, this review suggested that G-Rd in vivo can antagonize the reduced oxidative stress, regulate Ca²⁺, and inhibit inflammatory, resistance to apoptosis, and antipyroptosis on cerebral I/R damage. Collectively, G-Rd is a promising natural neuroprotective agent on cerebral I/R injury with unique advantages and a clear mechanism of action. More clinical randomized, blind-controlled trials are also needed to confirm the neuroprotective effect of G-Rd on cerebral I/R injury.

Figure 1

Chemical structures of G-Rd. G-Rd: ginsenoside-Rd.

Figure 2

Summary of the literature identification and selection process.

Figure 3

The pooled estimate of G-Rd on decrementing cerebral infarct volume after cerebral I/R damage. G-Rd: ginsenoside-Rd; I/R: ischemia/reperfusion.

Figure 4

The pooled estimate of G-Rd in the improvement of neurological function score (higher score means better recovery). G-Rd: ginsenoside-Rd.

Figure 5

The pooled estimate of G-Rd in the improvement of neurological function score (lower score means better recovery). G-Rd: ginsenoside-Rd.

Figure 6

Bias assessment plot for the effect of G-Rd on infarct volume by funnel blot (a) and Egger's test (b); neurological function score (lower score means better recovery) by funnel blot (c) and Egger's test (d). G-Rd: ginsenoside-Rd.

Figure 7

The neuroprotective mechanisms of G-Rd for I/R damage in experimental animal. MMP: mitochondrial membrane potential; NADH: nicotinamide adenine dinucleotide; MDA: malondialdehyde; GST: glutathione S-transferase; CAT: catalase; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; ROS: reactive oxygen species; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B cell inhibitor, alpha; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; MMP-9: neuroinflammation-mediated matrix metalloproteases-9; TNF-α: tumor necrosis factor alpha; IL-1β: interleukin 1β; IL-6: interleukin 6; iNOS: inducible nitric oxide synthase; COX-2: cyclooxygenase-2; BBB: the blood-brain barrier; MAPK: mitogen-activated protein kinase; SIRT1: sirtuin1; PARP-1: poly (ADP-ribose) polymerase-1; PAR: poly(ADP-ribose); AIF: apoptosis-inducing factor; PI3K: phosphatidylinositol 3-kinase; Akt: proteinserine-threonine kinase; ERK: extracellular regulated protein kinases; GSK-3b: glycogen synthase kinase-3b; Cyto C: cytochrome c; GLT-1: glial glutamate transporter-1; CaN: calcineurin; DAPK: death-associated protein kinase; NR2b: N-methyl-D-aspartate receptor 2B; NMDAR: N-methyl-d-aspartate receptor; TRPM 7: transient receptor potential melastatin-7; ASIC1a: acid sensing ion channels 1a; FoxO1: forkhead box transcription factor O1; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid-2-related factor 2; TXNIP: thioredoxin-interacting protein; NLRP3: nucleotide-binding oligomerization domain- (NOD-) like receptor 3; GSDMD: gasdermin D; G-Rd: ginsenoside-Rd; I/R: ischemia/reperfusion.