Schisandrin B, an active ingredient isolated from the fruit of Schisandra chinensis, increased serum and hepatic triglyceride levels in mice. In the present study, the effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice without and with the influence of fenofibrate were investigated. Parameters on hepatic index (the ratio of liver weight to body weight × 100) were also analyzed. Mice were intragastrically treated with schisandrin B at a single dose of 0.2, 0.4, 0.8, or 1.6 g/kg, without or with fenofibrate pretreatment (0.1 g/kg/day for 4 days, p.o.). Twenty-four hours after schisandrin B treatment, serum/hepatic triglyceride and total cholesterol levels were measured. Schisandrin B treatment dose-dependently increased serum and hepatic triglyceride levels as well as hepatic index in mice. In contrast, hepatic total cholesterol levels were decreased in a dose-dependent manner in schisandrin B-treated mice. Data obtained from effective kinetics analysis indicated that the action of schisandrin B on serum triglyceride had a higher specificity than those on hepatic total cholesterol and hepatic index. While fenofibrate pretreatment inhibited the schisandrin B-induced elevation in serum triglyceride levels, it completely abrogated the elevation of hepatic triglyceride levels in schisandrin B-treated mice. The combined treatment with schisandrin B and fenofibrate decreased hepatic total cholesterol level and increased the hepatic index in an additive or semi-additive manner, respectively. In conclusion, the results of effective kinetics analysis indicated that the schisandrin B-induced hypertriglyceridemia was competitively inhibited by fenofibrate. Schisandrin B may offer the prospect of setting up a mouse model of hypertriglyceridemia and fatty liver for screening triglyceride-lowering drug candidates.
Effects of tacrine and bis(7)-tacrine (0.25-20 lmol ⁄ kg, s.c.) on cognitive behaviour in cycloheximide (CYH)-treated mice were investigated. Cognitive behaviour was assessed by open-field test and step-through task with a 24-hr retention interval. Drugs or vehicle was given 30 min. prior to the first session. Although CYH treatment (110 mg ⁄ kg, i.p.) alone did not affect the locomotor activity of mice, CYH treatment in combination with tacrine (20 lmol ⁄ kg) decreased the locomotor activity by 37% in the acquisition session, when compared with mice treated with CYH alone. Bis-(7) tacrine cotreatment did not produce any detectable effect on locomotor activity. During the retention trial, tacrine (5 lmol ⁄ kg) or bis(7)-tacrine (1 lmol ⁄ kg) enhanced the retention latency (by 3.8-or 1.4-fold, respectively) in CYH-treated mice. In both training and retention trials, CYH treatment increased the number of footshocks (by 50% and 11.3-fold, respectively). However, during the retention (but not training) trial, tacrine (5 lmol ⁄ kg) or bis(7)-tacrine (1 lmol ⁄ kg) decreased the footshocks (by 8.6-fold or 39%, respectively) in CYH-treated mice. Combined treatment with CYH and bis(7)-tacrine (but not tacrine) resulted in an increased mortality rate in mice. The results indicated that tacrine and bis (7)-tacrine improved the amnesia caused by CYH treatment. However, the combined treatment with bis(7)-tacrine and CYH administration caused acute toxicity.Acetylcholine (ACh) is widely distributed in the central and peripheral nervous system. ACh released from cholinergic nerve terminals activates receptors at both pre-synaptic and post-synaptic sites. It is then hydrolysed by acetylcholinesterase (AChE) into choline and acetyl coenzyme A. Cholinergic nerve in the brain may play an important role in many cognitive functions, such as cortical modulation of sensory information processing, attention, memory and learning [1][2][3]. Therapeutic strategies adopting cholinergic precursor loading and AChE inhibitors, which can increase ACh concentration in vivo, were used for treating cognitive impairment occurring in Alzheimer's disease (AD) and geriatric memory dysfunction [4][5][6].The cognitive enhancement and AChE inhibition afforded by tacrine, a reversible AChE inhibitor, has been widely studied. The administration of tacrine is often accompanied by abnormal behaviour and a decline in physical strength in patients [7,8]. Bis(7)-tacrine is a novel anti-AD agent that can reversibly inhibit AChE 150-fold more potently than tacrine in rat brains [9,10]. The cognitive enhancement of bis(7)-tacrine was observed in rats treated with scopolamine, a muscarinic cholinergic receptor antagonist that causes memory loss, and AF64A, a cholinergic neuron-specific neurotoxin [11,12]. Our previous works have shown that both tacrine and bis(7)-tacrine inhibited the locomotor activity in normal mice and improved the impairment of open-field and passive avoidance response memory in mice treated with scopolamine [13][14][15]. Cycloheximi...
It is well established that cholinergic over-stimulation can interfere with memory processes. The aim of this study was to evaluate the effect of tacrine, an acetylcholinesterase inhibitor, on recognition memory as well as the associated hepatotoxicity in juvenile (20-day-old) and adult (100-day-old) ICR male mice. Recognition memory was assessed by open-field test and step-through task without footshocks for three sessions between 08:00 and 13:00, with a 24-hr retention interval. Tacrine (10 or 40 lmol ⁄ kg) or vehicle was administered (s.c.) 20 min. prior to the first session. During the acquisition session, tacrine suppressed the open-field behaviours, including locomotor activity, rearing, grooming and defecation (by 77-100%) in mice of both ages. During the recall (observable in both ages) and re-recall (observable in juvenile mice) session, the locomotor activity and rearing number were significantly increased, indicative of impairment in recognition memory, in mice treated with tacrine 40 lmol ⁄ kg. During the training trial, tacrine decreased the step-through number in mice of both ages. In contrast, during the retention and re-retention trials, the step-through number was increased (by 92% and 93%, respectively), indicative of impairment in step-through memory, in juvenile but not adult mice treated with tacrine 40 lmol ⁄ kg. Tacrine 40 lmol ⁄ kg elevated the serum alanine aminotransferase (ALT) activity (by 135%) in juvenile mice, but reduced the ALT activity (by 42%) in adult mice. The results indicated that 20-day-old mice seemed to be more sensitive than 100-day-old mice to tacrine-induced impairment in recognition memory and the associated liver damage.The cholinergic system in the brain is closely related to the regulation of learning and memory processes. However, studies have shown that cholinergic dysfunction, including insufficiency and hyperfunction caused by cholinergic agent, can impair the memory and behaviours. Patients suffering from Alzheimer's disease (AD) are characterized by cholinergic dysfunction in the brain, which eventually lead to a progressive memory loss and other cognitive symptoms that result in occupational and social disabilities [1,2]. Validated scales for clinical diagnosis of AD now take into consideration not only cognitive dimensions but also behavioural symptoms, with the introduction of behavioural psychological symptoms of dementia [3,4]. Ageing is accompanied by the decline in mental performance, including deficits in memory formation, learning and adaptation to novel environment, and the administration of cholinesterase inhibitors has been found to be useful in slowing the progression of the mild-to-moderate stage of AD or ageing with amnesia [5]. In this regard, micro-injections of tacrine or nicotine into the core of the nucleus accumbens were found to enhance the open-field habituation learning or memory [6,7]. On the other hand, tacrine is a nootropics that can produce amnesic effects in normal animals [8,9]. In addition, an open-field memory impai...
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