L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats
ABSTRACT The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (Aβ) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of Aβ pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The Aβ 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after Aβ injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30μg/2μl) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, Aβ treated rats showed delayed acquisition in a spatial reference memory task. Aβ treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30μg but not 3μg) and nimodipine (30μg). Calpain 2, caspase 12 and 3 were increased in the Aβ treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease.
SourceAvailable from: Hamid Gholamipour-Badie[Show abstract] [Hide abstract]
ABSTRACT: The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer's disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Aβ) 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.PLoS ONE 02/2015; 10(2):e0117555. DOI:10.1371/journal.pone.0117555 · 3.53 Impact Factor
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ABSTRACT: Semen Ziziphi Spinosae (SZS) has been used as a hypnotic-sedative medicine for thousands of years. Recently, SZS has also shown notable neuroprotective activities via anti-oxidative and anti-inflammatory effects in dementia animals. Jujuboside A (JuA), isolated from SZS, has been proved to be a major hypnotic-sedative component of SZS. In the present study, we firstly evaluated the effects of intracerebroventricular (ICV) injection of JuA (0.02 and 0.2mg/kg) for five consecutive days on cognitive impairment induced by ICV injection of Aβ1-42. The results showed that ICV treatment with JuA significantly mitigated learning and memory impairment in mice induced by Aβ1-42 as measured by the Y-maze, active avoidance and Morris water maze. Furthermore, ICV treatment with JuA reduced the level of Aβ1-42 in hippocampus, significantly inhibited the activities of acetylcholinesterase (AChE) and NO, and decreased the amount of the increased malondialdehyde (MDA) in the hippocampus and cerebral cortex of mice treated with ICV injection of Aβ1-42. Shrinkage of nuclei, swollen and eccentrically dispersed neuronal bodies were observed in hippocampus of AD mice induced by Aβ1-42, however, JuA noticeably improved the histopathological damage. Cumulatively, the present study indicates that JuA may serve as a potential therapeutic agent for the treatment of Alzheimer's disease.European Journal of Pharmacology 05/2014; 738. DOI:10.1016/j.ejphar.2014.05.041 · 2.68 Impact Factor
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ABSTRACT: Abstract The universality and vitality of calcium ions are implicit from its diverse physiological functions, from regulation of enzymes to synaptic plasticity and memory. However, overloading of these ions could result in life-threatening degenerative disorders. Calcium channels, which are involved in the transport of calcium ions, are targeted and blocked to prevent its overload, favoring vascular relaxation. Besides this primary action, calcium channel blockers (CCBs) also genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, especially of Alzheimer's type. Alzheimer's disease (AD) is triggered by the disruption of calcium homeostasis, which underlies the observed progressive cognitive decline that occurs in this neurodegenerative disorder. Fortunately, CCB is expected to offer neuroprotection and additionally demonstrate antiamyloid, antitau, antiphospholipase, antiplatelet, antioxidant, and anti-inflammatory activity, a solitary solution to all the subcellular physiological complications that are observed in AD. Therefore, the aim of this review was to unearth the prospective of CCB against cognitive frailty with a sole purpose of elucidating CCB as cognitive enhancers, which could find its use as a drug in prevention or treatment of AD.Reviews in the neurosciences 02/2014; 25(2). DOI:10.1515/revneuro-2013-0056 · 3.31 Impact Factor