Behavioural effects and regulation of PKCα and MAPK by huprine X in middle aged mice

Ratia, Miriam; Giménez-Llort, Lydia; Camps, Pelayo; Muñoz‐Torrero, Diego; Clos, MaV.; Badı́a, Albert

doi:10.1016/j.pbb.2010.03.013

Cited by 21 publications

(32 citation statements)

References 42 publications

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“…That improvement in the ‘day-by-day’ performance of the animals was due to a better ‘trial-by-trial’ performance on these days and a scanning-strategy choice in their search strategy as compared to random swimming observed in the saline-treated 3xTg-AD mice, which implies differences in their cognitive problem-solving approach. Indeed, these beneficial effects of huprine X in 3xTg-AD mice reinforce the procognitive results we have already demonstrated for this AChEI drug in normal ageing [17]. In previous studies, huperzine A had already shown its ability to relieve memory deficits in a number of different animal species with a clearly superior safety/efficacy ratio compared with other AChEIs [30].…”

Section: Discussionsupporting

confidence: 71%

“…As shown in figure 5, the two treatments increased the levels by approximately 20% of both metalloproteases in all cases, with the exception of the membrane fraction of the cortex of mice treated with huperzine A. Both the AChE inhibition and the known agonistic action on muscarinic M 1 receptors [14] may account for this effect as has previously been demonstrated in aged animals [17]. …”

Section: Resultsmentioning

confidence: 63%

“…However, our recent characterization of the behavioural effects of huprine X in middle-aged mice [17] has demonstrated a lack of these side effects following chronic administration. These results of huprine X are confirmed in the present work and also apply to huperzine A and to a different animal population affected by an AD-like pathology.…”

Section: Discussionmentioning

confidence: 99%

“…At the age of 7 months, the animals received chronic treatment with either huprine X (0.12 µmol·kg –1 ), huperzine A (0.80 µmol·kg –1 ) or saline at 15.00 h daily for 14 days and then the drug treatment continued throughout an additional 7-day period for behavioural testing. The chosen doses were those previously used in in vivo studies [17,23]. In each cage, animals were randomly selected to receive the doses of huprine X, huperzine A or saline.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, huprine X has an agonistic action upon muscarinic M 1 and nicotinic receptors [14,15], exhibits a tight-binding character in experiments of reversibility of bovine AChE inhibitory activity [12] and inhibits the amyloidogenic effect of AChE [16]. Furthermore, we have recently demonstrated that huprine X facilitates learning and memory in the Morris water maze test using middle-aged treated mice, and it also activates the downstream PKC/MAPK signalling pathways [17]. However, in vivo studies in animal models of memory deficiency remain to be undertaken.…”

Section: Introductionmentioning

confidence: 99%

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Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

et al. 2012

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Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer’s disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD). Methods: Seven-month-old homozygous 3xTg-AD male mice, which received chronic intraperitoneal treatment with either saline, huprine X (0.12 µmol·kg^–1) or huperzine A (0.8 µmol·kg^–1) were subjected to a battery of behavioural tests after 3 weeks of treatment and thereafter the brains were dissected to study the neurochemical effects induced by the two AChEIs. Results: Treatments with huprine X and huperzine A improved learning and memory in the Morris water maze and some indicators of emotionality without inducing important adverse effects. Moreover, huprine X and huperzine A activate protein kinase C/mitogen-activated protein kinase pathway signalling, α-secretases (ADAM 10 and TACE) and increase the fraction of phospho-glycogen synthase kinase 3-β. Conclusion: Results obtained herein using a sample of 3xTg-AD animals strongly suggest that the treatment with the two AChEIs not only improves the cognitive performance of the animals but also induces some neurochemical changes that could contribute to the beneficial effects observed.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

et al. 2012

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Novel Huprine Derivatives with Inhibitory Activity toward β‐Amyloid Aggregation and Formation as Disease‐Modifying Anti‐Alzheimer Drug Candidates

et al. 2010

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A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.

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Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice

et al. 2018

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Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer's disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.

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Behavioural effects and regulation of PKCα and MAPK by huprine X in middle aged mice

Cited by 21 publications

References 42 publications

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

Novel Huprine Derivatives with Inhibitory Activity toward β‐Amyloid Aggregation and Formation as Disease‐Modifying Anti‐Alzheimer Drug Candidates

Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice

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