Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

Abstract

The prevalence of Alzheimer’s disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.

Dihydropyridine Derivatives as Cell Growth Modulators In Vitro

“…A novel amphiphilic (lipophilic) 1,4-dihydropyridine derivative AP-12 (see Table 1 ) was studied in the present article as proliferation modifier in the above-mentioned cell systems. Recently, Jansone et al, 2016 [ 13 ], have described memory-improving, anxiolytic effects of this compound in transgenic AD model (TgAPPSweDI) male mice. It was also shown [ 12 ] that this compound crosses the blood-brain barrier and blocks neuronal (neuroblastoma) and vascular (vascular smooth muscle cell line) calcium channels, exerting Ca 2+ antagonistic properties, and changed brain protein expression (as postsynaptic membrane protein Homer-1), with a particular focus on those of the GABAergic system, and improved behavior.…”

“…Biological activity of some of these compounds was previously studied (for antioxidant diludine ([ 11 ], see as cited in [ 6 ]), amphiphilic 1,4-DHP derivative, MDR modifier and suitable gene (plasmid DNA) delivery agent in vitro K-2-11 [ 10 ], neuromodulator AP-12 [ 12 , 13 ], and also close compound Z41-74 [ 14 ] (see also Discussion part)). However, physiological activity profile for most of mentioned compounds has not been still determined and published.…”

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

“…Excessive Ca 2+ influx, which causes pathological signaling and gradual reduction of synaptic function and ultimately cell degeneration, was observed in patients with AD. Changes in Ca 2+ influx correlated with memory impairment in patients with AD ( Jansone et al, 2016 ). Memantine, which is a NMDAR antagonist and drug used in the treatment of AD, reduces the toxicity caused by excessive Ca 2+ in humans ( Lipton, 2005 ; Matsunaga et al, 2015 ; Kishi et al, 2017 ; Kabir et al, 2019 ).…”

Data for the cytotoxicity, self-assembling properties and synthesis of 4-pyridinium-1,4-dihydropyridines

“…Previously it was shown that related compound – 4-(N-dodecyl)pyridinium-1,4-DHPs demonstrated the ability to block brain calcium channels and improve memory by enhancing the GABAergic processes [8] .…”