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

Abstract

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.

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

“…M1-selective mAChR agonist AF267B and AF102B reduced cognitive deficits and decreased Ab and s pathologies in the cortex and hippocampus via ADAM17 in transgenic AD mouse model (Caccamo et al 2006;Fisher 2008;Welt et al 2015). Treatment with acetylcholinesterase inhibitors (AChEIs), huprine X and huperzine A, can improve the cognitive performance in transgenic AD mouse model, also through ADAM17 activation (Ratia et al 2013). Molecular chaperone phenylbutyric acid (PBA) treatment for 14 months in transgenic AD mouse model can enhance ADAM17 activity, followed by modified amyloid aggregation, decreased amyloid plaques and increased memory retention (Wiley et al 2011).…”

AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice

“…AVCRI104P3, (±)-3-chloro-12-[(3-{4-[(5,6-dimethoxyindan-2-yl)methyl] piperidin-1-yl}propyl) amino]-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b] quinoline [17] and huprine X, (±)-12-Amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline [25,26] were synthesized as previously described [20,21] at the Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona. The drugs were dissolved in a vehicle of 0.9% saline solution for chronic intraperitoneal injection in a volume of 1 mL kg −1 .…”

Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer’s Disease?

“…Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta) (Ratia et al, 2013). There is a long history of using H. serrata as a medicine in China to treat different kinds of disorders, including bruises, strains, swelling, rheumatism, schizophrenia, myasthenia gravis, and fever (Skolnick, 1997; Ma et al, 2007).…”

“…However, a number of recent studies have reported that this drug has “non-cholinergic” effects on AD (Ratia et al, 2013; Huang et al, 2014) in addition to the symptomatic, cognitive-enhancing effect of cholinesterase inhibition (Wang et al, 1986; Liu and Liu, 1995; Zhu and Giacobini, 1995). These new findings have greatly improved our understanding of pharmacological mechanisms of HupA in the treatment of AD.…”