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-1β 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.
Highlights
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 human immunodeficiency virus type 1 (HIV-1) is significantly higher than that of healthy people
Our recent study showed that intrahippocampal injection of CCL2 impaired learning memory and cognition in rats via apoptosis of hippocampal neurons [17], and rats with CCL2-induced cognitive disorder could be used as an ideal murine model to study the effect of CCL2 on HIV-associated neurocognitive disorder (HAND)
A rat model of CCL2-induced cognitive dysfunction successfully established by injecting CCL2 into the bilateral hippocampus of rats in our previous study was employed to determine the effects of Tanshinone IIA (Tan IIA) on CCL2-induced cognitive dysfunction, which shows a potential therapeutic approach of Tan IIA for HIVassociated neurocognitive disorder
Summary
CCL2 was first formulated into a mother liquor of 100 mg/L and diluted with sterile physiological saline to 1 mg/L. All rats apart from those in the control group underwent stereotactic injection to the bilateral hippocampus. E injection volume per side was 2.5 μl, and the sham surgery group was given an equal amount of sterile physiological saline. Anterior/posterior coordinates (− 3.7 mm), medial/lateral coordinates (±3.0 mm), and dorsal/ventral coordinates (− 3.0 mm) (from bregma and dura, flat skull) were selected according to the stereotaxic atlas of Franklin and Paxinos. An equal volume of sterile physiological saline was infused as a vehicle control. E needle was retained for 5 minutes after CCL2 or sterile physiological saline injection, the needle was slowly removed, and the pinhole was covered with a medical gelatin sponge to prevent the injection from overflowing. All rats were treated according to the experimental design (Figure 1)
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