Protective Effects of Ginsenoside Rb1 against Blood–Brain Barrier Damage Induced by Human Immunodeficiency Virus-1 Tat Protein and Methamphetamine in Sprague-Dawley Rats

Abstract

Although antiretroviral therapy has helped to improve the lives of individuals infected with human immunodeficiency virus 1 (HIV-1), these patients are often still afflicted with HIV-1-associated neurocognitive disorders, which can lead to neurocognitive impairment and even dementia, and continue to hamper their quality of life. Methamphetamine abuse in HIV-1 patients poses a potential risk for HIV-associated neurocognitive disorders, because methamphetamine and HIV-1 proteins such as transactivator of transcription can synergistically damage the blood-brain barrier (BBB). In this study, we aimed to examine the effects of methamphetamine and HIV-1 Tat protein on the blood-brain barrier function and to determine whether ginsenoside Rb1 (GsRb1) plays a role in protecting the BBB. Sprague-Dawley rats were divided into four groups. The experimental groups received methamphetamine and HIV-1 Tat protein or both and the control group received saline or GsRb1 pretreatment. Oxidative stress-related factors, tight junction (TJ) proteins, blood-brain barrier permeability, and morphological changes were recorded in each group. The results showed that the group treated with Methamphetamine[Formula: see text]Tat showed a significant change at the ultrastructural level and in the levels of oxidative stress-related factors, TJ proteins, and BBB permeability, suggesting that the BBB function was severely damaged by HIV-1 Tat and methamphetamine synergistically. However, malondialdehyde levels and BBB permeability were lower and the oxidative stress-related factors superoxide dismutase and glutathione were higher in the GsRb1-treated group than in the Methamphetamine[Formula: see text]Tat-treated group, indicating that GsRb1 can protect the BBB against the toxic effects of HIV-1 Tat and methamphetamine. These results show that GsRb1 may offer a potential therapeutic option for patients with HIV-associated neurocognitive disorders or other neurodegenerative diseases.

Methamphetamine and HIV-Tat Protein Synergistically Induce Oxidative Stress and Blood-Brain Barrier Damage via Transient Receptor Potential Melastatin 2 Channel

“…Previous studies have shown that METH-and HIV-Tat-induced injury to the BBB in SD rats is accompanied by a severe oxidative stress response (Li et al, 2018b). In this study, we found that METH and/or HIV-Tat decreased the CAT (Figure 2B), GSH-PX (Figure 2C), and SOD (Figure 2D) activities of the cells, while increased the ROS (Figure 2A) and MDA (Figure 2E) levels.…”

“…METH and HIV-Tatinduced synergistic damage to the BBB increase CNS exposure and the risk of HAND. Previous studies have demonstrated that METH and HIV-Tat can co-induce the oxidative stress response (Zeng et al, 2018), which has been shown to play an important role in BBB injury in rats (Li et al, 2018b). The exact mechanism for this process, however, remains unclear.…”

“…Several studies have shown that both METH and HIV-Tat can induce BMEC apoptosis (Ma et al, 2014;Jumnongprakhon et al, 2016;Jumnongprakhon et al, 2017;Qie et al, 2017), destroy the BMEC cytoskeleton (Avraham et al, 2004;Fernandes et al, 2014;Xue et al, 2019), reduce BMEC transepithelial electrical resistance (TEER) (Jumnongprakhon et al, 2016;Patel et al, 2017;Qie et al, 2017), and affect the expression and function of TJ proteins (Xu et al, 2012;Fernandes et al, 2014;Jiang et al, 2017b;Gonçalves et al, 2017;Qie et al, 2017;Xue et al, 2019), thus altering the BBB's permeability and destroying its structural integrity (Mcrae, 2016;Namyen et al, 2020). Moreover, when a combined exposure of both METH and HIV-Tat, the consequent BMEC damage and abnormal TJ protein expression are more serious (Patel et al, 2017;Li et al, 2018b). METH and HIV-Tatinduced synergistic damage to the BBB increase CNS exposure and the risk of HAND.…”

Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway

“…The neurotoxic activities of numerous HIV proteins, including Gp120, Tat, and Vpr, are also implicated in the neuropathogenic process (Mothobi and Brew, 2012). HIV-Tat (the transactivator of transcription) is a viral protein that compromises the blood-brain barrier permeability (Li et al, 2018) and causes alterations in inflammatory molecule production by interacting with cellular gene promoters and cellular receptors to induce apoptosis, autophagy, and cell death; this interaction may be one of the underlying mechanisms of HANDs (Rappaport et al, 1999; Bagashev and Sawaya, 2013; Fields et al, 2015).…”

Minor Ginsenoside Rg2 and Rh1 Attenuates LPS-Induced Acute Liver and Kidney Damages via Downregulating Activation of TLR4-STAT1 and Inflammatory Cytokine Production in Macrophages

“…Ginsenosides, the main active components of Panax ginseng Mayer ( P. ginseng ), are mainly classified into protopanaxadiol (PPD; Rb1, Rb2, Rb3, Rc, Rd, Rg3, and Rh2)- and protopanaxatriol (PPT; Re, Rg1, Rg2, and Rh1)-type saponins [ 12 ]. They have been shown to have various pharmacological effects, including anticancer and anti-inflammatory effects, and beneficial effects against cardiovascular diseases and immunodeficiency [ 13 , 14 , 15 , 16 ]. Among them, Rg1 attenuates hepatocellular apoptosis and inflammatory response in ischemia–reperfusion injury mouse models [ 17 ].…”