Butea superba Roxb. Extract Ameliorates Scopolamine-Induced Cognitive and Memory Impairment in Aged Male Rats

Butea superba Roxb. (B. superba) is a herb that has been used for rejuvenation, to improve sexual performance, or to prevent erectile dysfunction function. Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is the main cause of progressive dementia. This study aimed to investigate the amelioration for cognitive and memory dysfunction of B. superba ethanolic extract (BSE), a possible mechanism of action, and its toxicity. The results from the Y-maze test, novel object recognition test, and passive avoidance test exhibited that the administration of BSE at 50 mg/kg (BSL) and 200 mg/kg (BSH) could ameliorate scopolamine-induced cognitive impairment in all behavior testing. Moreover, BSE could prevent the cognitive deficit in a dose-dependent manner in a passive avoidance test. Furthermore, BSE inhibited acetylcholinesterase’s (AChE) ex vivo activity in the cerebral cortex and hippocampus. Also, the in vitro and ex vivo antioxidative effects of BSE revealed that BSE had free radical scavenging activities in both DPPH and FRAP assay. Furthermore, male rats treated with BSE at 200 mg/kg/day for two weeks could significantly increase serum testosterone compared with control ( P < 0.05 ). The GC-MS analysis and previous studies revealed that BSE contained propanoic acid, 3,3′-thiobis-, didodecyl ester, oleic acid, gamma-sitosterol, and stigmasterol which may play an important role in cognitive and memory impairment prevention. The toxicity test of BSE in rats at 50 and 200 mg/kg/day for two weeks showed that relative organ weight, serum creatinine, ALT, ALP, and CBC levels of both treated groups were not significantly different compared to the CON ( P > 0.05 ). These results suggest that BSE may not be toxic to the vital organ and blood. In conclusion, BSE has the potential to be developed as a health supplement product or medicine for AD prevention and treatment.

Neuroprotective Effects of Ceftriaxone Involve the Reduction of Aβ Burden and Neuroinflammatory Response in a Mouse Model of Alzheimer’s Disease

Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer’s disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aβ) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aβ deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aβ. Mice were injected bilaterally i.c.v. with Aβ fragment 25–35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aβ neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

Thiamine Alleviates Cognitive Impairment and Epileptogenesis by Relieving Brain Inflammation in PTZ-induced Kindling Rat Model

Epileptogenesis, the process by which the brain becomes epileptic, is related to neuroinflammation, hyperexcitability, and as a result cognitive deficits. Evidence suggests that therapeutic strategies targeting pathologic brain inflammation have emerged as a promising approach that prevents or disease-modifying therapy for epileptogenesis. Therefore, the PTZ kindling model of epilepsy was utilized to assess the neuroprotective role of thiamine in epileptogenesis. Male rats were exposed to PTZ-induced kindling and pretreated with low thiamine (25 mg/kg) or high thiamine (50 mg/kg). Cyclooxygenase (COX-1 and COX-2), interleukin 1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor-κB (NF-κB) concentrations in the brain were analyzed using biochemical assays. Cognitive function was evaluated using the passive avoidance test. Thiamine ameliorated epileptogenesis and enhanced the rats' performance in the passive avoidance test. Also, thiamine significantly decreased the level of neuroinflammatory mediators in the brain induced by PTZ. These results provide evidence that thiamine alleviates PTZ-induced neuroinflammation and cognitive impairments.

Intramyocardial Injection of Human Adipose-Derived Stem Cells Ameliorates Cognitive Deficit By Regulating Oxidative Stress-Mediated Hippocampal Damage After Myocardial Infarction

Cognitive impairment is a serious side effect of post-myocardial infarction (MI) course. We have recently demonstrated that human adipose-derived stem cells (hADSCs) ameliorated myocardial injury after MI by attenuating reactive oxygen species (ROS) levels. Here, we studied whether the beneficial effects of intramyocardial hADSC transplantation can extend to the brain and how they may attenuate cognitive dysfunction via modulating ROS after MI. After coronary ligation, male Wistar rats were randomized via an intramyocardial route to receive either vehicle, hADSC transplantation (1x106 cells), or the combination of hADSCs and 3-Morpholinosydnonimine (SIN-1, a peroxynitrite donor). Whether hADSCs migrated into the hippocampus was assessed by using human-specific primers in qPCR reactions. Passive avoidance test was used to assess cognitive performance. Postinfarction was associated with increased oxidative stress in myocardium, circulation and hippocampus. This was coupled with decreased numbers of dendritic spines as well as a significant downregulation of synaptic plasticity consisting of synaptophysin and PSD95. Step through latency during passive avoidance test was impaired in vehicle-treated rats after MI. Intramyocardial hADSC injection exerted therapeutic benefits in improving cardiac function and cognitive impairment. None of hADSCs were detected in rat’s hippocampus at the 3th day after intramyocardial injection. The beneficial effects of hADSCs on MI-induced histological and cognitive changes were abolished after adding SIN-1. MI-induced ROS attacked the hippocampus to induce neurodegeneration, resulting in cognitive deficit. The remotely intramyocardial administration of hADSCs, has the capacity of improved synaptic neuroplasticity in hippocampus mediated by ROS, not the cell engraftment, after MI.

Co-treatment With the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is a lethal progressive neurodegenerative disorder. Currently, many acetylcholinesterase inhibitors, such as donepezil, is widely used for the treatment of AD. However, the efficacy of long-term donepezil use is limited. SIP3, a mixture of Santalum album, Illicium verum, and Polygala tenuifolia, a new formula derived from traditional Korean herbal medicine. In this study, SIP3 were assessed the survival of Drosophila AD model and synergistic effect of SIP3, donepezil co-treatment of AD using APP/PS1 transgenic mice. Methods: In Drosophila AD models, we analyzed the survival, climbing ability and acridine orange (AO) staining. In APP/PS1 mice, at six months of age were randomized into four groups. Then, these groups were orally administered vehicle (for the control), donepezil, low and high doses SIP3 plus Donepezil respectively for six months. The passive avoidance test (PAT) and the Morris water maze (MWM) were analyzed cognitive behavioral changes. In addition, the forced swimming test (FST) and the tail suspension test (TST) were assessed depression-like behavior. To investigate the molecular and cellular mechanisms underlying positive effects of SIP3 on AD, the cerebral cortex transcriptomes were analyzed by RNA sequencing.Results: Using the passive avoidance test (PAT), we analyzed the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice, compared with the group treated with donepezil only, in late stage of AD. In addition, using the Morris water maze (MWM) test, co-treatment with donepezil and a low concentration of SIP3 significantly ameliorated cognitive impairment. Co-administration of SIP3 and donepezil effectively reduced depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of cerebral cortex transcriptome revealed that gene expression profiles after low dose of SIP3 co-treatment are slightly similar to those of normal phenotype mice than those obtained after donepezil treatment alone. Gene ontology (GO) along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway have demonstrated that differentially expressed genes were involved in locomotor behavior and neuroactive ligand-receptor interactions. Collectively: our results suggest that co-treatment of low dose of SIP3 and donepezil improves impaired learning, memory, and depression in late stage of AD in mice.

Effects of memantine on the passive avoidance test in young rats

Alzheimer’s disease (AD) is a long-lasting progressive neurodegenerative disease that degrades memory and cognitive function and is often complicated by disorientation and other psychiatric syndromes. At present, to improve the condition of patients with AD, for their treatment, use the drug memantine. The drug is a noncompetitive antagonist of NMDA glutamate receptors in the brain. The present experiments aimed to test the influence of memantine on the memory processes in rats. We used the passive avoidance test “Stepdown”. The latter is used to assess memory function based on the association formed between a particular environment that an animal is learning to avoid and a negative stimulus in the form of a weak electric shock to the feet. We found that memantine significantly, twice, decreased the latency time step-down from the platform in rats during their familiarization with the chamber. The rats became more determined and less afraid of the unknown environment under memantine. Memantine significantly affected the emotionality of young rats, which leads to errors in the passive avoidance test. However, it did not impair memory. It can be concluded that memantine induces a shift toward greater excitability in rats.

Cholinesterase Inhibitor 6-Chlorotacrine - In Vivo Toxicological Profile and Behavioural Effects

Background: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. Methods: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. Results: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. Conclusion: Observed effects predetermined 6-chlorotacrine as a potent parent compound for the synthesis of novel multifactorial drugs intended to the treatment of Alzheimer's disease. Even though 6- chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose the exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.