Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice

Li, Bin; Wanka, Lukas; Blanchard, Julie; Liu, Fei; Chohan, Muhammad Omar; Iqbal, Khalid; Grundke‐Iqbal, Inge

doi:10.1016/j.febslet.2010.06.025

Cited by 45 publications

(66 citation statements)

References 48 publications

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“…One-week treatment of rats with dimebon at a dose of 0.1 mkM/kg (0.32 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus. Because activation of structural plasticity and neurogenesis in the hippocampus is well demonstrated to be implicated in the mechanisms of contextual and spatial learning (Epp et al, 2007;Yang et al, 2008;Li et al, 2010;Pieper et al, 2010), we suggest that this effect might be one of the potential mechanisms which underlie the memory enhancing action of dimebon observed in the current study. Further experiments are required to address the possible link between the mnemonic effects of dimebon and its properties as a proneurogenic compound.…”

Section: Discussionmentioning

confidence: 60%

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Vignisse

Steinbusch

Bolkunov

et al. 2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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a b s t r a c t a r t i c l e i n f oPre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.

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Section: Discussionmentioning

confidence: 60%

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Vignisse

Steinbusch

Bolkunov

et al. 2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Lowering corticosterone secretion from midlife (Montaron et al 2006) or a midlife vitamin A supplementation (Touyarot et al 2013) for the rest of the animal's life prevents age-related spatial memory deficits and age-related decline in neurogenesis. In a young subject, pharmacological approaches, consisting of peripheral treatment with the cognitive enhancer ginseng (Qiao et al 2005), the peptidergic drug P21 (Li et al 2010), the histone acetyltransferases CBP/p300 (Chatterjee et al 2013), hippocampal gene transfer of VEGF (Cao et al 2004), blockade of NR2B-containing NMDAR (Hu et al 2008), stimulation of entorhinal cortex (Stone et al 2011a), or deletion of Toll-like receptors (TLRs) (Okun et al 2010), all promoted adult neurogenesis and facilitated memory performances in different learning tasks (contextual fear-conditioning paradigm, associative passive avoidance, and water maze).…”

Section: Correlationsmentioning

confidence: 99%

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

Abrous

Wojtowicz

2015

Cold Spring Harb Perspect Biol

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During the last decade, the questions on the functionality of adult neurogenesis have changed their emphasis from if to how the adult-born neurons participate in a variety of memory processes. The emerging answers are complex because we are overwhelmed by a variety of behavioral tasks that apparently require new neurons to be performed optimally. With few exceptions, the hippocampal memory system seems to use the newly generated neurons for multiple roles. Adult neurogenesis has given the dentate gyrus new capabilities not previously thought possible within the scope of traditional synaptic plasticity. Looking at these new developments from the perspective of past discoveries, the science of adult neurogenesis has emerged from its initial phase of being, first, a surprising oddity and, later, exciting possibility, to the present state of being an integral part of mainstream neuroscience. The answers to many remaining questions regarding adult neurogenesis will come along only with our growing understanding of the functionality of the brain as a whole. This, in turn, will require integration of multiple levels of organization from molecules and cells to circuits and systems, ultimately resulting in comprehension of behavioral outcomes.

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“…Peptidergic neurotrophic compounds based on ciliary neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF) are among the most promising drug candidates [150-152]. A CNTF peptidergic compound was found to successfully rescue the dentate gyrus neurogenesis and rescue neuronal/synaptic plasticity in aged mice [151, 153, 154], in a 3xTg-AD transgenic mouse model of AD [26], in an AAV1-I 2NTF-CTF rat model of sporadic AD [77], and in Ts65Dn trisomic Down syndrome mouse model [155]. In all these studies the chronic treatment with CNTF peptidergic compounds showed a significant improvement in cognitive performance and no side effects were found.…”

Section: Therapeutic Attempts That Failed and Therapeutic Approachmentioning

confidence: 99%

Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

Iqbal

Liu

Chen

2014

Biochemical Pharmacology

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The bulk of AD research during the last twenty-five years has been Aβ-centric based on a strong faith in the Amyloid Cascade Hypothesis which is not supported by the data on humans. To date, Aβ-based therapeutic clinical trials on sporadic cases of AD have been negative. Although most likely the major reason for the failure is that Aβ is not an effective therapeutic target for sporadic AD, initiation of the treatment at mild to moderate stages of the disease is blamed as too late to be effective. Clinical trials on presymptomatic familial AD cases have been initiated with the logic that Aβ is a trigger of the disease and hence initiation of the Aβ immunotherapies several years before any clinical symptoms would be effective. There is an urgent need to explore targets other than Aβ. There is now increasing interest in inhibiting tau pathology, which does have a far more compelling rationale than Aβ. AD is multifactorial and over 99% of the cases are the sporadic form of the disease. Understanding of the various etiopathogenic mechanisms of sporadic AD and generation of the disease-relevant animal models are required to develop rational therapeutic targets and therapies. Treatment of AD will require both inhibition of neurodegeneration and regeneration of the brain.

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Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice

Cited by 45 publications

References 48 publications

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

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