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Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder.

ABSTRACT: Chemokine CC motif ligand 2 (CCL2) is one of the most recognized proinflammatory chemokines, and the expression of CCL2 in the cerebrospinal fluid of patients infected with HIV-1 is significantly higher than that of healthy people. As such, it is seen as an important cause of HIV-associated neurocognitive disorder (HAND). Our previous investigation has confirmed the pathological role of CCL2 in mediating brain damage leading to cognitive dysfunction. Currently, however, research on therapeutic drugs for the central nervous system targeting CCL2 is very limited. Our present study used brain stereotactic technology to induce cognitive impairment in rats by injecting CCL2 (5?ng) into the bilateral hippocampus. To investigate the protective effect and mechanism of Tanshinone IIA (25, 50, 75?mg/kg/d) on CCL2-induced learning memory and cognitive impairment in rats, we performed the Morris water maze (MWM) and novel object recognition tests (NORT) on the rats. The results showed that Tanshinone IIA significantly alleviated CCL2-induced learning memory and cognitive dysfunction. Further studies on the hippocampal tissue of the rats revealed that Tanshinone IIA treatment significantly increased the activity of SOD and GSH-Px while the level of MDA decreased compared to the model group. Additionally, the relative expression of apoptosis-associated genes caspase-3, caspase-8, and caspase-9 and inflammation-associated genes IL-1? and IL-6 in Tanshinone IIA-treated rats was lower than that in model rats. Finally, we confirmed hippocampal neuron loss and apoptosis by Nissl staining and TdT-mediated dUTP Nick end labeling (TUNEL). Taken together, these data imply that Tanshinone IIA can ameliorate CCL2-induced learning memory and cognitive impairment by impacting oxidative stress, inflammation, and apoptosis. Tanshinone IIA may be a potential therapeutic agent for the treatment of HAND.

SUBMITTER: Liao YJ

PROVIDER: S-EPMC7060416 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder.

Liao Yuan-Jun YJ Chen Jian-Min JM Long Jiang-Yi JY Zhou Yi-Jun YJ Liang Bing-Yu BY Zhou Yan Y

BioMed research international 20200222

Chemokine CC motif ligand 2 (CCL2) is one of the most recognized proinflammatory chemokines, and the expression of CCL2 in the cerebrospinal fluid of patients infected with HIV-1 is significantly higher than that of healthy people. As such, it is seen as an important cause of HIV-associated neurocognitive disorder (HAND). Our previous investigation has confirmed the pathological role of CCL2 in mediating brain damage leading to cognitive dysfunction. Currently, however, research on therapeutic d ...[more]

PMID: 32185196

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Project description:Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut-brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation.

Project description:BackgroundNeuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathic disease associated with the anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions primarily located on the optic nerves and spinal cord. Tanshinone IIA (TSA), an active natural compound extracted from Salvia miltiorrhiza Bunge, has profound immunosuppressive effects on neutrophils.ObjectiveThe present study aimed to evaluate the effect of TSA on NMOSD mice and explore the underlying mechanisms. Mice were initially administered TSA (pre-TSA group, n = 20) or vehicle (vehicle group, n = 20) every 8?h for 3 days, and then NMOSD model was induced by intracerebral injection of NMOSD-immunoglobulin G (NMO-IgG) and human complement (hC). In addition, post-TSA mice (n = 10) were administered equal dose of TSA at 8?h and 16?h after model induction. At 24?h after intracerebral injection, histological analysis was performed to assess the inhibitory effects of TSA on astrocyte damage, demyelination, and neuroinflammation in NMOSD mice, and western blotting was conducted to clarify the effect of TSA on the NF-?B and MAPK signaling pathways. Furthermore, flow cytometry and western blotting were conducted to verify the proapoptotic effects of TSA on neutrophils in vitro.ResultsThere was a profound reduction in astrocyte damage and demyelination in the pre-TSA group and post-TSA group. However, prophylactic administration of TSA induced a better effect than therapeutic treatment. The number of infiltrated neutrophils was also decreased in the lesions of NMOSD mice that were pretreated with TSA. We confirmed that prophylactic administration of TSA significantly promoted neutrophil apoptosis in NMOSD lesions in vivo, and this proapoptotic effect was mediated by modulating the caspase pathway in the presence of inflammatory stimuli in vitro. In addition, TSA restricted activation of the NF-?B signaling pathway in vivo.ConclusionOur data provide evidence that TSA can act as a prophylactic agent that reduces NMO-IgG-induced damage in the mouse brain by enhancing the resolution of inflammation by inducing neutrophil apoptosis, and TSA may serve as a promising therapeutic agent for neutrophil-associated inflammatory disorders, such as NMOSD.

Dataset Information

Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder.

Publications

Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder.

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