A guanidine-appended scyllo-inositol derivative AAD-66 enhances brain delivery and ameliorates Alzheimer’s phenotypes

Lee, Dohyun; Lee, Woo-Sirl; Lim, Sungsu; Kim, Yun Kyung; Jung, Hoe‐Yune; Das, Subhashis; Lee, Juhyun; Luo, Wenjie; Kim, Kyong‐Tai; Chung, Sung‐Kee

doi:10.1038/s41598-017-14559-7

Cited by 21 publications

(20 citation statements)

References 33 publications

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“…Further concerns about SI safety have led to the development of SI derivatives, aiming to increase brain penetration, allowing for better efficacy with lower doses of SI for treating AD. A recent report has highlighted AAD-66, a guanidine-appended SI derivative that has improved cognitive performance in a 5xFAD mouse model of AD, concomitant with a reduction in Aβ deposition and glial reactivity as compared to free SI when both were administered ad libitum at the same dose [ 203 ].…”

Section: Neurodegenerative Diseases: Perspectives For the Use Of Imentioning

confidence: 99%

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

López-Gambero

Sanjuan²,

Serrano-Castro

et al. 2020

Biomedicines

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Inositols are sugar-like compounds that are widely distributed in nature and are a part of membrane molecules, participating as second messengers in several cell-signaling processes. Isolation and characterization of inositol phosphoglycans containing myo- or d-chiro-inositol have been milestones for understanding the physiological regulation of insulin signaling. Other functions of inositols have been derived from the existence of multiple stereoisomers, which may confer antioxidant properties. In the brain, fluctuation of inositols in extracellular and intracellular compartments regulates neuronal and glial activity. Myo-inositol imbalance is observed in psychiatric diseases and its use shows efficacy for treatment of depression, anxiety, and compulsive disorders. Epi- and scyllo-inositol isomers are capable of stabilizing non-toxic forms of β-amyloid proteins, which are characteristic of Alzheimer’s disease and cognitive dementia in Down’s syndrome, both associated with brain insulin resistance. However, uncertainties of the intrinsic mechanisms of inositols regarding their biology are still unsolved. This work presents a critical review of inositol actions on insulin signaling, oxidative stress, and endothelial dysfunction, and its potential for either preventing or delaying cognitive impairment in aging and neurodegenerative diseases. The biomedical uses of inositols may represent a paradigm in the industrial approach perspective, which has generated growing interest for two decades, accompanied by clinical trials for Alzheimer’s disease.

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Section: Neurodegenerative Diseases: Perspectives For the Use Of Imentioning

confidence: 99%

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

López-Gambero

Sanjuan²,

Serrano-Castro

et al. 2020

Biomedicines

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“…Further, sI prevents tau hyperphosphorylation (Jin and Selkoe, 2015). These potentially beneficial effects have prompted development of sI and close sI analogs as potential treatments for AD/ADRD (Salloway et al, 2011;Morrone et al, 2016;Lee et al, 2017;Liu et al, 2018). A possible mechanism to explain the low sI signal in supraphysiologic-dose AAS users is that its synthetic enzyme, inositol epimerase, which converts myo-inositol to sI, may be inhibited by AAS.…”

Section: Supraphysiologic-dose Aas Exposures Are Associated With Neurmentioning

confidence: 99%

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

Kaufman

Kanayama

Hudson

et al. 2019

Neuroscience & Biobehavioral Reviews

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Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain β-amyloid (Aβ) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aβ and tau-P. Aβ and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.

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“…BACE1 is the ␤ secretase implicated in AD and inhibitors of this enzyme are verubecestat MK8931 [142,143]; AZD-3293(LY-3314814) [144,145]; AtabecestatJNJ-54861911 [146,147]; E-2609 [148]; BI-1181181 [145,149]; inhibitor of ␥-secretaseareEVP-0962 [150,151]; and BMS-932481 [152]. Recently developed compounds which prevent aggregation of A␤ are GV-971 [153]; ALZT-OP1 [154]; Phenserine [155]; Posiphen [156,157]; Scyllo-Inositol [158,159]; ALZ-801 [160]; SAN-61 [161] and Exebryl-1 [162].…”

Section: Anti-amyloid Drugs In Clinical Trialsmentioning

confidence: 99%

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Duggal

Mehan

2019

ADR

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Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

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A guanidine-appended scyllo-inositol derivative AAD-66 enhances brain delivery and ameliorates Alzheimer’s phenotypes

Cited by 21 publications

References 33 publications

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

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