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Tetramethylpyrazine Ameliorates Isoflurane‑Induced Cognitive Dysfunction by Inhibiting Neuroinflammation Via Mir‑150 in Rats

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3878 EXPERIMENTAL AND THERAPEUTIC MEDICINE 20: 3878-3887, 2020 Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats HUAQING CUI*, ZHONGHUI XU* and CHUNSHAN QU Department of Anesthesia and Perioperative Medicine, Dongying Hospital of Traditional Chinese Medicine, Dongying, Shandong 257055, P.R. China Received September 11, 2019; Accepted July 10, 2020 DOI: 10.3892/etm.2020.9110 Abstract. Tetramethylpyrazine (TMP) has neuroprotective Introduction effects in the pathogenesis of some human diseases, such as Parkinson's disease. The present study aimed to investigate the Anesthetic-induced cognitive dysfunction is a frequent role of TMP in isoflurane‑induced cognitive dysfunction in rats, complication following major surgery (1), and the typical and further identify the mechanisms involved in the protec- symptoms include memory deficits and impaired infor- tive effects of TMP. The Morris water maze test was used to mation processing after surgery. Some patients with evaluate the cognitive function of rats exposed to isoflurane or anesthetic-induced cognitive dysfunction can regress, but treated with TMP. ELISA was conducted to evaluate the effects an increasing number of cases have been found to involve of isoflurane or TMP on neuroinflammation. The expression long‑term cognitive dysfunction that leads to a significantly of microRNA-150 (miR-150) was measured using reverse decreased quality of life in patients (2). For example, it is transcription-quantitative PCR, and the potential target genes reported that ~30-50% patients suffer from postoperative of miR‑150 were predicted and verified. The impaired cogni- cognitive dysfunction after cardiac surgery, and only 45% of tive function induced by isoflurane in the rats was significantly them can recover to baseline cognitive function by one year ameliorated by treatment with TMP. In addition, TMP treatment after surgery (3). Isoflurane is a generally used anesthetic that in rats attenuated neuroinflammation caused by isoflurane. The has been reported to induce cognitive dysfunction in patients expression of miR‑150 was inhibited by isoflurane exposure, after surgery (4). Previous studies have provided evidence but was enhanced by TMP treatment in rats. Furthermore, the for neuroinflammation as a key event in the pathogenesis of overexpression of miR‑150 alleviated the isoflurane‑induced isoflurane‑induced cognitive dysfunction (5). For example, cognitive dysfunction and neuroinflammation, while the neuro- increased inflammatory cytokines have been observed to protective effects of TMP were significantly abrogated by the be induced by anesthesia in brain after surgery (6), and knockdown of miR-150. AKT3 was a direct target of miR-150, isoflurane‑induced cognitive dysfunction can be attenuated and its mRNA expression was significantly decreased by the by suppressing neuroinflammation (7). overexpression of miR-150 in isoflurane- and TMP-treated Tetramethylpyrazine (TMP) is an alkaloid extracted rats. These results demonstrated the protective effects of TMP from the roots of Ligusticum chuanxiong Hort (8), and has against isoflurane‑induced cognitive dysfunction, which were important biological actions, including anti-inflammatory, achieved by attenuating neuroinflammation via the regulation cardioprotective, antioxidant, immune-enhanced and neuro- of the miR-150/AKT3 pathway. In addition, miR-150 may serve protective effects (9,10). Moreover, TMP has been reported as a novel therapeutic target for the alleviation of cognitive to exert a neuroprotective role in Parkinson's disease (11) dysfunction induced by anesthetics. and cerebral ischemia/reperfusion (12). However, whether TMP can also improve the cognitive dysfunction induced by isoflurane remains unknown. Previous studies have revealed that TMP can improve certain diseases by inhibiting inflam- matory reactions, especially neuroinflammation. For example, Correspondence to: Dr Chunshan Qu, Department of Anesthesia Fu et al (13) found an antidepressant effect of TMP in a chronic and Perioperative Medicine, Dongying Hospital of Traditional unpredictable mild stress mouse model via the suppression Chinese Medicine, 107 Beier Road, Dongying, Shandong 257055, of the Toll‑like receptor 4 inflammatory signaling pathway. P. R. Ch i na In addition, Wang et al (14) demonstrated that TMP exerts a E-mail: [email protected] protective role against traumatic brain injury by attenuating *Contributed equally neuroinflammation. Thus, it was hypothesized that TMP may regulate the inflammatory reaction in isoflurane-induced Key words: tetramethylpyrazine, isoflurane, cognitive dysfunction, cognitive dysfunction. inflammation, microRNA-150 MicroRNAs (miRNAs/miRs) are a group of small non-coding RNAs with extensive biological function in various human diseases, such as metabolic homoeostasis (15). CUI et al: NEUROPROTECTIVE ROLE OF TETRAMETHYLPYRAZINE 3879 Numerous miRNAs have been identified as key molecules After treatment, five rats from each group were subjected to in neurodevelopment, such as miR-200a and miR-302c (16). the Morris water maze test to evaluate the cognitive function, In addition, certain miRNAs exhibit neuroprotective effects and hippocampi were collected from the remaining five rats by regulating neuroinflammation (17). miR-150 has been after sacrifice by cervical dislocation. suggested to be an inhibitor of neuroinflammation (18), and it can ameliorate neuropathic pain by targeting AKT3, which is Morris water maze performance. This study evaluated a major regulator of the inflammatory response (19). However, the cognitive function of the rats using a Morris water to the best of our knowledge, the relationship between miR-150 maze test, which was performed using a method previously and anesthetic-induced cognitive dysfunction has rarely been described (23). Briefly, 48 h post‑isoflurane exposure, the rats reported. in each group were subjected to the hidden-platform training Previous studies have examined the role of miRNAs in for 5 days with 2 trials per day, and the platform was removed the protective mechanisms of traditional Chinese herbal on the 6th day. A computerized tracking system (Actimetrics medicines in various human diseases, such as miR-294 (20). software version 2.6; Actimetrics) was used to monitor the To investigate novel approaches to attenuate the impairment trials, and the performance, including latency to find the in cognition induced by isoflurane, the present study aimed to hidden platform, distance traveled, time spent in each quadrant evaluate the protective role of TMP against isoflurane‑induced and number of platform crossing, of the rats in different groups cognitive dysfunction in rats, and to further identify the was recorded and compared. After the test, the rats (weight, underlying mechanism by assessing the role of miR-150 and 250-300 g) were sacrificed by cervical dislocation under its effects on neuroinflammation. anesthesia with 50 mg/kg pentobarbitone. Materials and methods ELISA. The expression levels of the pro‑inflammatory cyto- kines IL-1β (cat. no. RLB00), IL-6 (cat. no. R6000B) and Animals and exposure to isoflurane. In total, 100 male TNF-α (cat. no. RTA00) in the hippocampus collected from Sprague-Dawley at 7 weeks of age (220-260 g) rats were the rats in each group were detected using the rat ELISA kit purchased from the Animal Center of Chinese Academy of (Invitrogen; Thermo Fisher Scientific, Inc.), following the Sciences, and were housed in animal facilities with free access manufacturer's instruction. to water and food under a standard environment (25±1°C, 60-65% humidity and 12/12 h light/dark cycle). The rats RNA extraction and reverse transcription‑quantitative PCR were randomly designed into two groups: Control (n=10) and (RT‑qPCR). Total RNAs in the hippocampus were extracted isoflurane groups (n=90). For isoflurane exposure, the rats using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, were housed in anesthetic chambers containing 2% isoflurane Inc.), which were then used for RT to synthesize cDNA using (Sigma-Aldrich; Merck KGaA) mixed with 100% oxygen for the PrimeScript RT reagent kit (Takara Bio, Inc.) according 4 h. The rats in the control group were placed in the animal to the manufacturer's protocols, the conditions were 37˚C for facilities with room air. All the animal experiments were in 15 min and 98˚C for 5 min. Hippocampal expression levels of accordance with the guidelines of the National Institutes of miR-150 and the mRNA expression of AKT3 were measured Health and Association for Assessment and Accreditation using RT-qPCR, which was performed using a SYBR green I of Laboratory Animal Care (21), and were approved by the Master Mix kit (Invitrogen; Thermo Fisher Scientific, Inc.) on Animal Care and Use Committee of Dongying Hospital of a 7500 Real-Time PCR system (Applied Biosystems; Thermo Traditional Chinese Medicine Hospital. Fisher Scientific, Inc.). The PCR conditions were as follows: 95˚C for 5 min, followed by 40 cycles of 95˚C for 30 sec, 60˚C Animal treatment. The rats that received isoflurane exposure for 30 sec, and 72˚C for 40 sec and then a final extension at 72˚C were further assigned to eight groups (10 rats/group): Isoflurane for 5 min. The final expression levels were calculated using the + DMSO vehicle, isoflurane + TMP, isoflurane + miR‑negative 2-ΔΔCq method (24) and normalized to U6 or GAPDH. Primers control (miR‑NC), isoflurane + miR‑150 mimic, isoflurane
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