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Neurotherapeutic Effects of Pueraria mirifica Extract in Early- and Late-Stage Cognitive Impaired Rats

Anukulthanakorn K, Parhar IS, Jaroenporn S, Kitahashi T, Watanbe G, Malaivijitnond S

Phytother Res, 2016 Jun;30(6):929-39.
PMID: 26915634 DOI: 10.1002/ptr.5595

We determined the neurotherapeutic effects of Pueraria mirifica extract (PME) and pure puerarin (PU) in comparison with 17β-estradiol (E2 ) in early- and late-stage cognitive impaired rats. Rats were ovariectomized (OVX), kept for 2 and 4 months to induce early- and late-stage cognitive impairment, respectively, and divided into four groups that were treated daily with (i) distilled water, (ii) 100 mg/kg of PME, (iii) 7 mg/kg of PU, and (iv) 80 µg/kg of E2 for 4 months. The estrogen deficiency symptoms of OVX rats were abrogated by treatment with E2 or PME, but not by treatment with PU. The mRNA level of genes associated with amyloid production (App and Bace1) and hyperphosphorylated Tau (Tau4) were upregulated together with the level of impaired cognition in the 2- and 4-month OVX rats. Treatment with E2 reduced the level of cognitive impairment more than that with PME and PU, and 2-month OVX rats were more responsive than 4-month OVX rats. All treatments down-regulated the Bace1 mRNA level in 2-month OVX rats, while PU and PME also decreased the App mRNA level in 2- and 4-month OVX rats, respectively. Only PU suppressed Tau4 expression in 2-month OVX rats. Thus, PME and PU elicit neurotherapeutic effects in different pathways, and earlier treatment is optimal. Copyright © 2016 John Wiley & Sons, Ltd.

Matched MeSH terms: Cognition Disorders/drug therapy*
Fulltext Carbohydrates for improving the cognitive performance of independent-living older adults with normal cognition or mild cognitive impairment

Ooi CP, Loke SC, Yassin Z, Hamid TA

Cochrane Database Syst Rev, 2011 Apr 13;2011(4):CD007220.
PMID: 21491398 DOI: 10.1002/14651858.CD007220.pub2

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate state between normal cognition and dementia in which daily function is largely intact. This condition may present an opportunity for research into the prevention of dementia. Carbohydrate is an essential and easily accessible macronutrient which influences cognitive performance. A better understanding of carbohydrate-driven cognitive changes in normal cognition and mild cognitive impairment may suggest ways to prevent or reduce cognitive decline.
OBJECTIVES: To assess the effectiveness of carbohydrates in improving cognitive function in older adults.
SEARCH STRATEGY: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register on 22 June 2010 using the terms: carbohydrates OR carbohydrate OR monosaccharides OR disaccharides OR oligosaccharides OR polysaccharides OR CARBS. ALOIS contains records from all major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trial databases and grey literature sources.
SELECTION CRITERIA: All randomised controlled trials (RCT) that have examined the efficacy of any form of carbohydrates in normal cognition and MCI.
DATA COLLECTION AND ANALYSIS: One review author selected and retrieved relevant articles for further assessment. The remaining authors independently assessed whether any of the retrieved trials should be included. Disagreements were resolved by discussion.
MAIN RESULTS: There is no suitable RCT of any form of carbohydrates involving independent-living older adults with normal cognition or mild cognitive impairment.
AUTHORS' CONCLUSIONS: There are no suitable RCTs on which to base any recommendations about the use of any form of carbohydrate for enhancing cognitive performance in older adults with normal cognition or mild cognitive impairment. More studies of many different carbohydrates are needed to tease out complex nutritional issues and further evaluate memory improvement.

Matched MeSH terms: Cognition Disorders/drug therapy*
Fulltext In Silico and In Vitro Analysis of Bacoside A Aglycones and Its Derivatives as the Constituents Responsible for the Cognitive Effects of Bacopa monnieri

Ramasamy S, Chin SP, Sukumaran SD, Buckle MJ, Kiew LV, Chung LY

PLoS One, 2015;10(5):e0126565.
PMID: 25965066 DOI: 10.1371/journal.pone.0126565

Bacopa monnieri has been used in Ayurvedic medicine to improve memory and cognition. The active constituent responsible for its pharmacological effects is bacoside A, a mixture of dammarane-type triterpenoid saponins containing sugar chains linked to a steroid aglycone skeleton. Triterpenoid saponins have been reported to be transformed in vivo to metabolites that give better biological activity and pharmacokinetic characteristics. Thus, the activities of the parent compounds (bacosides), aglycones (jujubogenin and pseudojujubogenin) and their derivatives (ebelin lactone and bacogenin A1) were compared using a combination of in silico and in vitro screening methods. The compounds were docked into 5-HT1A, 5-HT2A, D1, D2, M1 receptors and acetylcholinesterase (AChE) using AutoDock and their central nervous system (CNS) drug-like properties were determined using Discovery Studio molecular properties and ADMET descriptors. The compounds were screened in vitro using radioligand receptor binding and AChE inhibition assays. In silico studies showed that the parent bacosides were not able to dock into the chosen CNS targets and had poor molecular properties as a CNS drug. In contrast, the aglycones and their derivatives showed better binding affinity and good CNS drug-like properties, were well absorbed through the intestines and had good blood brain barrier (BBB) penetration. Among the compounds tested in vitro, ebelin lactone showed binding affinity towards M1 (Ki = 0.45 μM) and 5-HT2A (4.21 μM) receptors. Bacoside A and bacopaside X (9.06 μM) showed binding affinity towards the D1 receptor. None of the compounds showed any inhibitory activity against AChE. Since the stimulation of M1 and 5-HT2A receptors has been implicated in memory and cognition and ebelin lactone was shown to have the strongest binding energy, highest BBB penetration and binding affinity towards M1 and 5-HT2A receptors, we suggest that B. monnieri constituents may be transformed in vivo to the active form before exerting their pharmacological activity.

Matched MeSH terms: Cognition Disorders/drug therapy*
Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial

Lee LK, Shahar S, Chin AV, Yusoff NA

Psychopharmacology (Berl), 2013 Feb;225(3):605-12.
PMID: 22932777 DOI: 10.1007/s00213-012-2848-0

RATIONALE: Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer's disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI).
OBJECTIVES: This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI.
METHODS: This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n = 18) or placebo (n = 18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate.
RESULTS: The fish oil group showed significant improvement in short-term and working memory (F = 9.890; ηp (2) = 0.254; p

Matched MeSH terms: Cognition Disorders/drug therapy*
Chronic cerebral hypoperfusion-induced memory impairment and hippocampal long-term potentiation deficits are improved by cholinergic stimulation in rats

Damodaran T, Müller CP, Hassan Z

Pharmacol Rep, 2019 Jun;71(3):443-448.
PMID: 31003155 DOI: 10.1016/j.pharep.2019.01.012

BACKGROUND: Chronic cerebral hypoperfusion (CCH) can induce the accumulation of reactive oxygen species, which leads to oxidative damage, neuronal injury, and central cholinergic dysfunction in vulnerable regions of the brain, such as the hippocampus and cerebral cortex. These effects can lead to significant cognitive impairments in clinical populations of vascular dementia (VaD). The present studies aimed to investigate the role of the cholinergic system in memory functions and hippocampal long-term potentiation (LTP) impairments induced by CCH in rats.
METHODS: Male Sprague Dawley rats were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham surgery. Then, PBOCCA rats received ip injections with, either vehicle (control group), the muscarinic receptor agonist oxotremorine (0.1 mg/kg), or the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg). Cognitive functions were evaluated using a passive avoidance task and the Morris water maze test. In addition, hippocampal LTP was recorded in vivo under anaesthesia.
RESULTS: The PBOCCA rats exhibited significant deficits in passive avoidance retention and spatial learning and memory tests. They also showed a suppression of LTP formation in the hippocampus. Oxotremorine and physostigmine significantly improved the learning and memory deficits as well as the suppression of LTP in PBOCCA rats.
CONCLUSIONS: The present data suggest that the cholinergic system plays an important role in CCH-induced cognitive deficits and could be an effective therapeutic target for the treatment of VaD.

Matched MeSH terms: Cognition Disorders/drug therapy*
Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice

Ibrahim NF, Yanagisawa D, Durani LW, Hamezah HS, Damanhuri HA, Wan Ngah WZ, et al.

J Alzheimers Dis, 2017;55(2):597-612.
PMID: 27716672

Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

Matched MeSH terms: Cognition Disorders/drug therapy*