Neurokinin 3 Receptor Effects on Cognitive Behaviour in a Rat Model of Alzheimer's Disease

Abstract Alzheimer's disease (AD) is accepted as a form of progressive and irreversible dementia. It is known that cholinergic systems are commonly affected in AD. Neurokinin 3 receptor (NK3R) is involved in learning and memory related processes. Activation of NK3R is known to facilitate the release of many neurotransmitters such as acetylcholine (Ach), dopamine (DA), noradrenaline (NA). Based on this information, hypothesis of the study that NK3R agonism can have positive effects on behavioral and learning parameters through cholinergic and catecholaminergic mechanisms. The aim of this study was to investigate the effects of NK3R agonist senktide on cognitive and neurobehavioral mechanisms in model of AD.50 adult male Wistar albino rats were obtained; Control, AD, Control+NK3R agonist, AD+NK3R agonist, AD+NK3R agonist+antagonist groups. AD model was established by administering Aβ1-42 intracerebroventricularly. Following NK3R agonist+antagonist injections, open field (OF) and Morris water maze (MWM) were applied for behavioral and learning parameters. Hippocampus and cortex tissues were extracted. Analysis of cholinergic mechanisms from these tissues were performed by ELISA method.Group-time effect was significant in OF (p<0.05). Distance moved parameter was significant between groups in MWM (p<0.05). There was a significant difference between groups in AChE and ChAT levels (p<0.05). DA concentrations of brainstem samples were significant (p<0.05). There was no significant difference in NA concentration (p>0.05). NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. It has been observed that positive effects on learning and memory performances can be mediated by cholinergic mechanisms.

Download Full-text

Yishen Huazhuo Decoction Induces Autophagy to Promote the Clearance of Aβ1-42 in SAMP8 Mice: Mechanism Research of a Traditional Chinese Formula Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200604174223 ◽

2020 ◽

Vol 19 (4) ◽

pp. 276-289

Author(s):

Kai Wang ◽

Weiming Sun ◽

Jiachun Xu ◽

Qijing Qin ◽

Zhen Yu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Neuronal Loss ◽

Tunel Staining ◽

Initiation Increase ◽

Apoptosis Index ◽

Significant Difference ◽

Related Proteins ◽

Samp8 Mice

Background: Studies have found that autophagy could promote the clearance of Aβ. To promote and maintain the occurrence of autophagy in Alzheimer's disease (AD) might be a potential way to reduce neuronal loss and improve the learning and memory of AD. Objective: To investigate the possible mechanisms of Yishen Huazhuo Decoction (YHD) against AD model. Methods: Forty 7-month-old male SAMP8 mice were randomly divided into model (P8) group and YHD group, 20 in each group, with 20 SAMR1 mice as control (R1) group. All mice were intragastrically administered for 4 weeks, YHD at the dosage of 6.24g/kg for YHD group, and distilled water for P8 group and R1 group. Morris water maze (MWM) test, Nissl’s staining, TEM, TUNEL staining, immunofluorescence double staining, and western blot analysis were applied to learning and memory, structure and ultrastructure of neurons, autophagosome, apoptosis index, Aβ, LAMP1, and autophagy related proteins. Results: The escape latency time of YHD group was significantly shorter on the 4th and 5th day during MWM test than those in P8 group (P=0.011, 0.008<0.05), and the number of crossing platform in YHD group increased significantly (P=0.02<0.05). Nissl’s staining showed that the number of neurons in YHD group increased significantly (P<0.0001). TEM showed in YHD group, the nucleus of neurons was slightly irregular, with slightly reduced organelles, partially fused and blurred cristae and membrane of mitochondria. The apoptosis index of YHD group showed a decreasing trend, without statistically significant difference (P=0.093>0.05), while Caspase3 expression in YHD group was significantly lower (P=0.044<0.05). YHD could promote the clearance of Aβ1-42 protein, improve the expression of Beclin-1 and p-Bcl2 proteins, reduce mTOR and p62 proteins. Conclusions: YHD could induce autophagy initiation, increase the formation of autophagosomes and autolysosome, promote the degradation of autophagy substrates, thereby to regulate autophagy, thereby to promote the clearance of Aβ1-42 to improve memory impairment in SAMP8 mice.

Download Full-text

Therapy of Dredging the Bowels Enhanced the Neuroprotective Effect of Nourishing Kidney Herbs on Hippocampal Cholinergic System in Alzheimer’s Disease Model Rat Induced by Aβ 1-42

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3282385 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Lu-Da Feng ◽

Yang Tian ◽

Xin Wang ◽

Run Dai ◽

Song Cai ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Cholinergic System ◽

Neuroprotective Effect ◽

Disease Model ◽

Memory Deficits ◽

Underlying Mechanism ◽

Chat Activity ◽

Significant Difference

Background. Therapy of nourishing kidney has been used for treating memory deficits of Alzheimer’s disease (AD) for thousands of years based on traditional Chinese medicine. However, we found the therapy of dredging the bowels could alleviate both memory deficits and mental symptoms of AD in clinic. Objective. To determine whether the therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs for treating AD rats, and to explore the underlying mechanism of the combination of nourishing kidney and dredging the bowels (NKDB) herbs. Methods. 60 rats were randomly divided into sham-operated group (SOG), model group (MG), nourishing kidney group (NKG), dredging the bowels group (DBG), nourishing kidney and dredging the bowels group (NKDBG), and donepezil hydrochloride group (DHG). The model establishment was performed by injecting Aβ 1-42 into the hippocampal CA1 region. Animals received aqueous solution of Chinese herbal medicine or western medicine while SOG received only distilled water. Ability of learning and memory were assessed by Morris water maze. Acetylcholinesterase(AChE) and choline acetyltransferase (ChAT) activity and positive cells in the hippocampus were detected by the biochemical and immunofluorescent assay. Results. All rats were in the same baseline. While after model establishment, ability of learning and memory of MG, NKG, DBG, NKDBG, and DHG were significantly impaired compared with SOG. Whereas after treatment, ability of learning and memory of NKG, DBG, NKDBG, and DHG were significantly improved compared with MG. Additionally, AChE activity of NKG, DBG, and NKDBG was significantly decreased, meanwhile ChAT activity showed an increased tendency. The number of AChE-positive cells and ChAT-positive cells of both NKDBG and DHG were significantly decreased and increased respectively, superior to those when compared with NKG and DBG. What’s more, there was no significant difference between NKDBG and DHG. Conclusion. Therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs by reversing morphological damage of hippocampal cholinergic system. Furthermore, treatment with NKDB herbs could be effectively against AD, providing a practical therapeutic strategy in clinic.

Download Full-text

Characteristics of Insulin-degrading Enzyme in Alzheimer's Disease: A Meta-Analysis

Current Alzheimer Research ◽

10.2174/1567205015666180119105446 ◽

2018 ◽

Vol 15 (7) ◽

pp. 610-617 ◽

Cited By ~ 4

Author(s):

Huifeng Zhang ◽

Dan Liu ◽

Huanhuan Huang ◽

Yujia Zhao ◽

Hui Zhou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Enzyme Activity ◽

Protein Level ◽

Senile Plaque ◽

Meta Analysis ◽

Cochrane Library ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Significant Difference

Background: β-amyloid (Aβ) accumulates abnormally to senile plaque which is the initiator of Alzheimer's disease (AD). As one of the Aβ-degrading enzymes, Insulin-degrading enzyme (IDE) remains controversial for its protein level and activity in Alzheimer's brain. Methods: The electronic databases PubMed, EMBASE, The Cochrane Library, OVID and Sinomed were systemically searched up to Sep. 20th, 2017. And the published case-control or cohort studies were retrieved to perform the meta-analysis. Results: Seven studies for IDE protein level (AD cases = 293; controls = 126), three for mRNA level (AD cases = 138; controls = 81), and three for enzyme activity (AD cases = 123; controls = 75) were pooling together. The IDE protein level was significantly lower in AD cases than in controls (SMD = - 0.47, 95% CI [-0.69, -0.24], p < 0.001), but IDE mRNA and enzyme activity had no significant difference (SMD = 0.02, 95% CI [-0.40, 0.43] and SMD = 0.06, 95% CI [-0.41, 0.53] respectively). Subgroup analyses found that IDE protein level was decreased in both cortex and hippocampus of AD cases (SMD = -0.43, 95% CI [-0.71, -0.16], p = 0.002 and SMD = -0.53, 95% CI [-0.91, -0.15], p = 0.006 respectively). However, IDE mRNA was higher in cortex of AD cases (SMD = 0.71, 95% CI [0.14, 1.29], p = 0.01), not in hippocampus (SMD = -0.26, 95% CI [-0.58, 0.06]). Conclusions: Our results indicate that AD patients may have lower IDE protease level. Further relevant studies are still needed to verify whether IDE is one of the factors affecting Aβ abnormal accumulation and throw new insights for AD detection or therapy.

Download Full-text

Cognitive behaviour therapy (CBT) for depressed carers of people with Alzheimer's disease and related disorders

10.1002/14651858.cd001748.pub2 ◽

2005 ◽

Author(s):

G Charlesworth ◽

J Riordan ◽

L Shepstone

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Behaviour Therapy ◽

Behaviour Therapy ◽

Cognitive Behaviour

Download Full-text

Donepezil Combined with DL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild to Moderate Alzheimer’s Disease: A Multicenter, Prospective Cohort Study

Journal of Alzheimer s Disease ◽

10.3233/jad-201381 ◽

2021 ◽

Vol 80 (2) ◽

pp. 673-681

Author(s):

Jin Wang ◽

Xiaojuan Guo ◽

Wenhui Lu ◽

Jie Liu ◽

Hong Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Logistic Regression ◽

Regression Analysis ◽

Cohort Study ◽

Prospective Cohort ◽

Daily Living ◽

Multivariate Logistic Regression Analysis ◽

Multivariate Logistic Regression ◽

Significant Difference

Background: Vascular factors and mitochondria dysfunction contribute to the pathogenesis of Alzheimer’s disease (AD). DL-3-n-butylphthalide (NBP) has an effect in protecting mitochondria and improving microcirculation. Objective: The aim was to investigate the effect of donepezil combined NBP therapy in patients with mild-moderate AD. Methods: It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n = 43) or the donepezil combined NBP group (n = 49) for 48 weeks. All patients were evaluated with Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog), Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using multivariate logistic regression analysis. Results: The multivariate logistic regression analysis showed that the changes of ADAS-cog score (OR = 2.778, 95% CI: [1.087, 7. 100], p = 0.033) and ADCS-ADL score (OR = 2.733, 95% CI: [1.002, 7.459], p = 0.049) had significant difference between donepezil alone group and donepezil combined NBP group, while the changes of NPI (OR = 1.145, 95% CI: [0.463, 2.829], p = 0.769), MMSE (OR = 1.563, 95% CI: [0.615, 3.971], p = 0.348) and CIBIC-plus (OR = 2.593, 95% CI: [0.696, 9.685], p = 0.156) had no significant difference. The occurrence of AEs was similar in the two groups. Conclusion: Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment.

Download Full-text

Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200266 ◽

2021 ◽

Vol 5 (1) ◽

pp. 49-53

Author(s):

Steven Lehrer ◽

Peter H. Rheinstein

Keyword(s):

Breast Cancer ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apoe Genotype ◽

Uk Biobank ◽

Breast Cancer Patients ◽

Apoe4 Allele ◽

Significant Difference ◽

The Uk ◽

Cognitive Problems

Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

Download Full-text

Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-03102-3 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Zahra Ayati ◽

Guoyan Yang ◽

Mohammad Hossein Ayati ◽

Seyed Ahmad Emami ◽

Dennis Chang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Function ◽

Daily Living ◽

Randomised Clinical Trials ◽

Disease Assessment ◽

Significant Difference

Abstract Background Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well-known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti-dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia. Methods An electronic database search of some major English and Chinese databases was conducted until 31st May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev-Man 5.3 software was applied to perform the meta-analyses. Results A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales such as ADAS-cog and CDR-SB. Saffron improved daily living function, but the changes were not statistically significant. No serious adverse events were reported in the included studies. Conclusions Saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.

Download Full-text