Mechanism of Mongolian Medicine Eerdun Wurile in Improving Postoperative Cognitive Dysfunction Through Activation of the PI3K Signaling Pathway

ObjectiveTo study the effect of Eerdun Wurile (EW), a traditional Mongolian medicine, on the cognitive function of rats by activating the IRS-PI3K-AKT-GLUT4 pathway in an animal model of postoperative cognitive dysfunction (POCD).MethodsFifty clean-grade adults Sprague Dawley (SD) male rats were assigned to one of five groups: (1) a control group with no anesthesia (Group C), (2) a POCD model group with anesthesia only (Group P), (3) POCD group with low-dose EW treated (Group L), (4) a POCD group with high-dose EW treated (Group H), and (5) a POCD model group with dexmedetomidine treated (Group D) for positive control. The study started 7 days after all rats had acclimated to housing. Rats were trained in the Morris Water Maze navigation 5 days before surgery. All rats underwent the same maze for navigation and spatial exploration experiments on the preoperative day 1 and postoperative days 1, 3, 5, and their learning and memory abilities were assessed. At the end of the water maze experiment, rats were sacrificed to obtain hippocampal tissue. The mRNA levels of IRS-2, PI3K, AKT, and GLUT4 were measured in the hippocampus by real-time PCR, and the expression of IRS-2, PI3K, AKT, and GLUT4 protein in the hippocampus was determined by Western blotting to investigate the potential mechanisms at the molecular level.ResultsCompared to control Group C, Group P, L, H, and D showed prolonged escape latency (P < 0.05) and decreased number of times to cross the platform (P < 0.05) at 1, 3 and 5 days after surgery. Compared to Group P, Group L, H, and D showed a decrease in escape latency with an increased number of crossing the platform at all-time points after surgery (P < 0.05). Within individual P, L, H, and D groups, escape latencies decreased (P < 0.05) and the number of times that the platform was crossed increased (P < 0.05) between postoperative days 3 and 5 compared to postoperative 1 day. Compared to Group C, the mRNA expression of IRS-2, PI3K, AKT and GLUT4 in the hippocampus of P, L, H, and D groups were decreased (P < 0.05). Compared to Group P, IRS-2, PI3K, AKT, and GLUT4 in the hippocampus of L, H, and D groups were increased (P < 0.05). Compared with Group D, the expression levels of IRS-2 and AKT in both L and H groups were higher. The expression level of PI3K in Group L was also higher (P < 0.05) vs Group D. The expression of AKT mRNA in Group H was higher than in Group L (P < 0.05). Compared to Group C, the p-IRS-2/IRS-2 ratio in the hippocampus of Group P was higher than that of Group C (P < 0.05). Compared to Group P, the ratios of p-IRS-2/IRS-2 in Group L, Group H, and Group D were lower, and the ratios of the p-PI3K/PI3K, p-AKT/AKT, and p-GLUT4/GLUT4 were higher (P < 0.05).ConclusionAdministration of EW showed the effect on the signaling pathway in rats with POCD. The therapeutic effect was better in the low-dose group. This could be related to the insulin downstream signal molecule PI3K and the IRS-PI3K-AKT-GLUT4 signaling pathway.

Up-And-Down γ-Synuclein Transcription in Dopamine Neurons Translates Into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

Neuroprotective Effects of Probiotic-Supplemented Diet on Cognitive Behavior of 3xTg-AD Mice

Alzheimer’s disease (AD) is recognized as one of the most common types of senile dementia. AD patients first suffer memory loss for recent events (short-term memory impairment). As the disease progresses, they are deprived of self-awareness. This study aims to explore the effects of a probiotic-supplemented diet on the cognitive behaviors and pathological features of mouse models of Alzheimer’s disease (AD). Mice in the control group and the 3xTg-AD group were fed a regular diet and a probiotic-supplemented diet, respectively, for 20 weeks. Behavioral experiments like Morris’s water maze and Y maze were conducted. Then, feces of mice were collected for 16S sRNA gene sequencing for microorganisms. In the end, soluble and insoluble Aβ40 and Aβ42 in the hippocampus and cortex of mice in each group were quantitatively analyzed with a double-antibody Sandwich ELISA. The expression levels of tau protein and gliocyte in the hippocampus and cortex were detected using the Western Blot method. The result of the Morris water maze experiment indicated that, in the place navigation test, the mice in the 3xTg-AD group experienced a significant decline in the learning ability and a longer escape latency and in the space exploration test, the swimming time of mice in the 3xTg-AD group in the target quadrant decreased and after being treated with the probiotic diet, mice in the 3xTg-AD group had improved learning and memory ability. The result of Y maze showed that the probiotic diet can improve the spontaneous alternation accuracy of mice in the 3xTg-AD group. The result of 16s rRNA gene sequencing showed that, compared with mice in the WT group, those in the 3xTg-AD group experienced a change in the intestinal flora. The Western Blot result displayed a decreased expression level of tau (pS202) ( P < 0.05 ) and decreased expression levels of Iba-1 and GFAP ( P < 0.05 ). The result of the ELISA experiment showed decreased levels of soluble and insoluble Aβ40 and Aβ42 in 3xTg-AD mice ( P < 0.05 ). In conclusion, a probiotic diet can prevent and treat AD by improving the intestinal flora of 3xTg-AD.

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions.

Evaluation effects of “An Tri Khang” hard capsule on scopolamine-induced memory impairment in experimental animals

This study was performed to investigate the effects of An Tri Khang (ATK) hard capsule on scopolamine-induced memory impairment in experimental animals. The effects on memory of oral administration ATK were evaluated on scopolamine-induced memory impairment in experimental animals. The memory improvement effects were conducted on 2 experimental models: the Morris water maze (MWM) and the Multi-T maze (MTM). In the MWM model, ATK significantly reduced the time spent and pathlength to platform, increased the percentage of time swimming in platform’s quadrant. Swiss mice performed the MTM with shorter in both the time spent and the pathlength to the goal box (p < 0.01). Both doses of ATK attenuated scopolamine-mediated impairment of memory. ATK has potential effects on memory improvement. It is suggested that further clinical trials should be undertaken to have thorough assessment on human.

The β-Secretase Substrate Seizure 6–Like Protein (SEZ6L) Controls Motor Functions in Mice

The membrane protein seizure 6–like (SEZ6L) is a neuronal substrate of the Alzheimer’s disease protease BACE1, and little is known about its physiological function in the nervous system. Here, we show that SEZ6L constitutive knockout mice display motor phenotypes in adulthood, including changes in gait and decreased motor coordination. Additionally, SEZ6L knockout mice displayed increased anxiety-like behaviour, although spatial learning and memory in the Morris water maze were normal. Analysis of the gross anatomy and proteome of the adult SEZ6L knockout cerebellum did not reveal any major differences compared to wild type, indicating that lack of SEZ6L in other regions of the nervous system may contribute to the phenotypes observed. In summary, our study establishes physiological functions for SEZ6L in regulating motor coordination and curbing anxiety-related behaviour, indicating that aberrant SEZ6L function in the human nervous system may contribute to movement disorders and neuropsychiatric diseases.

Effects of Omega-3 Polyunsaturated Fatty Acids on Cognitive Function after Splenectomy in Rats

Background. Postoperative cognitive dysfunction (POCD) is a common complication after abdominal surgery. Several studies have reported that POCD is related to neuroinflammation caused by surgery. Omega-3 polyunsaturated fatty acids (PUFAs) can effectively inhibit the systematic inflammatory response. So, we use fish oil to study the effect of fish oil on inflammation, immunity, and cognitive behavior after splenectomy in rats. Methods. 60 SD (Sprague-Dawley) rats were randomly divided into control group (group C, n = 20 ), surgery group (group S, n = 20 ), and omega-3 (fish oil) intervention group (group F, n = 20 ). Omega-3 PUFA was injected intraperitoneally from 3 days before operation to 7 days after operation in group F, and normal saline was injected simultaneously in group S. Rats in group S and group F received splenectomy under general anesthesia. Morris water maze behavioral evaluation was performed on the first, third, fifth, and seventh day after operation. The levels of IL-1β (interleukin-1β), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), SOD (superoxide dismutase), and GSH-PX (glutathione peroxidase) were detected. Results. Serums IL-1β, IL-6, and TNF-α concentrations in group S and group F were higher than those in group C ( P < 0.01 ), while those inflammatory cytokines in group F were significantly lower than those in group S ( P < 0.01 ); serum GSH-PX levels in group F were higher than group S ( P < 0.01 ). The Morris water maze behavior test performance of group F was better than that of group S ( P < 0.05 ). Conclusion. Omega-3 PUFA can effectively improve postoperative inflammatory response, reduce the damage of antioxidant defense system, and improve postoperative cognitive function.