Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat

Background and purpose:

The beneficial effect of 5-HT₆ receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT₆ receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.

Experimental approach:

The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.

Key results:

Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.

Conclusions and implications:

These data suggest a potential therapeutic role of 5-HT₆ receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer''s disease and schizophrenia.     

补肾壮阳胶囊对小鼠认知功能障碍的改善作用及机制研究

目的：本文从补肾壮阳胶囊（WSKY）改善精神分裂症模型小鼠认知功能障碍进行研究,以探究其可能的作用机制。方法：采用地卓西平马来酸盐（MK-801）建立精神分裂症模型。动物行为学方面,运用Morris水迷宫实验评价补肾壮阳胶囊对精神分裂症小鼠认知功能障碍的治疗效应;组织生物化学方面,运用实时荧光定量PCR（RT-PCR）和蛋白免疫印迹（Western blot）的方法考察补肾壮阳胶囊对脑源性神经营养因子（BDNF）、钙调蛋白激酶Ⅱ（CaMKⅡ）、环腺苷酸反应元件结合蛋白（CREB）的mRNA和细胞外信号调节激酶（ERK）蛋白表达的影响。结果：WSKY中、高剂量组小鼠Morris水迷宫定位航行逃避潜伏期小于模型组,而其空间探索穿过原平台所在位置的次数、在原平台所在象限搜索的时间百分比均大于模型组（P<0.05）;WSKY中、高剂量可以增加BDNF mRNA的含量和ERK蛋白的表达。结论：WSKY中、高剂量可以改善精神分裂症小鼠的认知功能障碍,其作用机制与WSKY提高精神分裂症小鼠海马区BDNF mRNA的表达和增加ERK蛋白含量有关。     

Neurobehavioral effects of chronic dietary and repeated high-level spike exposure to chlorpyrifos in rats.

This study aimed to model long-term subtoxic human exposure to an organophosphorus pesticide, chlorpyrifos, and to examine the influence of that exposure on the response to intermittent high-dose acute challenges. Adult Long-Evans male rats were maintained at 350 g body weight by limited access to a chlorpyrifos-containing diet to produce an intake of 0, 1, or 5 mg/kg/day chlorpyrifos. During the year-long exposure, half of the rats in each dose group received bi-monthly challenges (spikes) of chlorpyrifos, and the other half received vehicle. Rats were periodically tested using a neurological battery of evaluations and motor activity to evaluate the magnitude of the acute response (spike days) as well as recovery and ongoing chronic effects (non-spike days). Effects of the spikes differed as a function of dietary level for several endpoints (e.g., tremor, lacrimation), and in general, the high-dose feed groups showed greater effects of the spike doses. Animals receiving the spikes also showed some neurobehavioral differences among treatment groups (e.g., hypothermia, sensory and neuromotor differences) in the intervening months. During the eleventh month, rats were tested in a Morris water maze. There were some cognitive deficits observed, demonstrated by slightly longer latency during spatial training, and decreased preference for the correct quadrant on probe trials. A consistent finding in the water maze was one of altered swim patterning, or search strategy. The high-dose feed groups showed more tendency to swim in the outer annulus or to swim very close to the walls of the tank (thigmotaxic behavior). Overall, dietary exposure to chlorpyrifos produced long-lasting neurobehavioral changes and also altered the response to acute challenges.     

Neonatal exposure to higher brominated diphenyl ethers, hepta-, octa-, or nonabromodiphenyl ether, impairs spontaneous behavior and learning and memory functions of adult mice.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants, have been shown to be increasing in the environment and in human mother's milk. We have earlier reported that lower brominated PBDEs, such as tetra-, penta-, and hexa-brominated diphenyl ethers, can cause developmental neurotoxic effects in mice. Recently, this was also observed with the full-brominated PBDE, deca-brominated diphenyl ether (PBDE 209), although it was suggested that the effects were caused by a (possibly debrominated) metabolite thereof. The present study revealed that 2,2',3,3',4,4',5,5',6-nonabromodiphenyl ether (PBDE 206), 2,2',3,4,4',5,5',6-octabromodiphenyl ether (PBDE 203), and to a minor extent also 2,2',3,4,4',5',6'-heptabromodiphenyl ether (PBDE 183) can induce developmental neurotoxic effects. Neonatal Naval Medical Research Institute male mice were exposed on postnatal day 3 or 10 to PBDE 206, PBDE 203, or PBDE 183, given as a single oral dose of 21 mumol/kg body weight. At the adult age of 2-3 months, the mice were observed for performance in a spontaneous behavior test and the Morris water maze test. PBDE 203 and PBDE 206, when administered on neonatal day 10, caused disturbances in spontaneous behavior, leading to disrupted habituation and a hyperactive condition in adults at the age of 2 months. These behavioral changes were also seen in 2-month-old mice exposed to PBDE 203 on neonatal day 3. Furthermore, exposure to PBDE 203 on neonatal day 10 affected learning and memory functions in adult mice. The developmental neurotoxic effects were most pronounced in mice exposed to PBDE 203. These developmental neurobehavioral defects were in agreement with those we observed previously with lower brominated PBDEs and with PBDE 209. It is important to consider the fact that different PBDE congeners can have differing degrees of potency, when comparing levels of PBDEs in the environment and in mother's milk.     

Hesperidin,a citrus flavonoid,protects against l-methionine-induced hyperhomocysteinemia by abrogation of oxidative stress,endothelial dysfunction and neurotoxicity in Wistar rats

Context: Hesperidin (HSP), a flavanoglycone found in citrus fruits, has antioxidant, anti-inflammatory and neuroprotective properties.

Objective: This study evaluates the protective effect of HSP on l-methionine-induced hyperhomocysteinemia (HHcy) in rats.

Materials and methods: Male Wistar rats were randomly divided into seven groups as DMSO, l-methionine, HSP (25, 50 and 100?mg/kg), HSP-per se (100?mg/kg) and donepezil (0.1?mg/kg). HHcy was induced by oral administration of l-methionine (1.7?g/kg) for 32 days. From the 14^th day of study HSP (25, 50 and 100?mg/kg) and donepezil was administered orally to l-methionine-treated rats. Cognitive impairment induced by HHcy was determined using the Morris water maze (MWM) and Y-maze on video tracking system (28^th–32^nd day). Different biomarkers of HHcy in serum and brain and vascular reactivity were evaluated and histopathology (thoracic aorta and brain) was done.

Results: HSP (100?mg/kg) treatment in l-methionine-treated rats exhibited significant (p?p?l-methionine on acetylcholine-induced endothelial-dependent relaxation and increased serum nitrite and vascular nitric oxide bioavailability along with the restoration of histological aberrations.

Conclusion: HSP exerts a protective effect on HHcy by abrogating oxidative stress, ED and neurotoxicity.     

Symptomatic effect of donepezil,rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model

Rationale APP23 mice are a promising model of Alzheimers disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients.Objectives To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia.Methods Animals were tested at an age at which untreated APP23 mice display severe deficits in visual–spatial learning. Four-month-old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg^–1), rivastigmine (0.5 or 1.0 mg kg^–1), galantamine (1.25 or 2.5 mg kg^–1), memantine (2 or 10 mg kg^–1) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing.Results All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg^–1, rivastigmine 0.5 mg kg^–1 and donepezil 0.3 mg kg^–1. Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose–response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial.Conclusions This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.