Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues

The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1–11 and 12–16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1–11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC₅₀ (eqBuChE) = 2.9 ± 0.4 μM; IC₅₀ (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC₅₀ (EeAChE) = 0.61 ± 0.04 μM; IC₅₀ (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer’s disease.     

树鼩中脑腹侧被盖区向尾状核的DOPA能和AChE阳性纤维投射研究

应用荧光逆行标记分别与荧光组化(FAGLU)和AChE-药理组化相结合技术,研究了树鼩中脑腹侧被盖区向尾状核头部的DOPA能和ACHE-阳性纤维投射。结果表明:树鼩中脑腹侧被盖区除分别向同侧和对侧尾状核头部发出DOPA能纤维投射外,还向同侧尾状核头部发出AChE阳性投村纤维;此外,腹侧被盖区存在着向双侧尾核头部发出分叉投射纤维的DOPA能细胞。     

Antioxidant and antiacetylcholinesterase activities of chard (Beta vulgaris L. var. cicla)

Plants have been used for many years as a source of traditional medicine to treat various diseases and conditions. Many of these medicinal plants are also excellent sources for phytochemicals, many of which contain potent antioxidant and antiacetylcholinesterase activities. Chard (Beta vulgaris L. var. cicla) is widely spread in Turkey and used as an antidiabetic in traditional medicine. In the present study, the antioxidant activity and acetylcholinesterase inhibitor capacity of chard were examined. In addition, proline level of chard was determined. The antioxidant activity of water extract of chard was evaluated using different antioxidant tests. The results were compared with natural and synthetic antioxidants. The results suggest that chard may provide a natural source of antioxidant and antiacetylcholinesterase activities and proline content.     

On the specificity of the acetylcholinesterase defect in dystrophic mice

The tetrameric form of acetylcholinesterase (AChE) in ReJ/129 dystrophic mice was demonstrated to be absent from endplate-poor regions of skeletal muscle but present in endplate-rich regions. Skeletal muscle secreted normal amounts of this form of AChE. Visceral organs had normal amounts and distribution of the AChE molecular forms. These results suggest that the AChE defect in dystrophic mice is limited to skeletal muscle, and the defect does not reflect an abnormality of AChE synthesis but probably reflects an inability to incorporate the enzyme into skeletal muscle membranes.     

Toxicological responses of Cyprinus carpio exposed to the herbicide penoxsulam in rice field conditions

Cyprinus carpio fish were exposed to penoxsulam (Ricer) in field conditions. The experiment in the rice field was carried out for 7, 21 and 72 days. Oxidative stress parameters and antioxidant profile were studied. The acetylcholinesterase (AChE) enzyme activity in the brain was increased after 7 days and reduced after 21 and 72 days of the experiment in the rice field. The AChE activity in muscle was reduced only after 72 days of exposure. Thiobarbituric acid-reactive species were increased in the liver, brain and muscle at 7 days of the trial, reduced at 21 days in the brain and unaltered after 72 days of exposure in muscle. However, an increase in this parameter in the brain and liver was observed. Liver glutathione S-transferase was reduced at 7 days, unchanged at 21 days and increased after 72 days of exposure. Catalase of the liver changed only in the second experimental period, when it was reduced. Liver protein carbonyl was reduced at 7 days and increased at 21 and 72 days of exposure. This study shows long-term effects of rice herbicide at environmentally relevant concentrations on toxicological parameters in different tissues (brain, muscle and liver) of Cyprinus carpio.     

Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats

It is shown that l-3-n-butylphthalide (l-NBP), the isomer of dl-NBP (racemic 3-n-butylphthalide, a new anti-cerebral ischemic agent) significantly attenuated cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. In the present study, l-NBP (10 and 30 mg/kg) long-term (3-month) treatment of aged rat (21-month-old) significantly improved the learning and memory capability measured by the Morris water maze test. Hematoxylin–eosin-stained slices showed that both l-NBP at 30 mg/kg, and memantine as control at 20 mg/kg, attenuated the neurodegenerative changes in aged rats. l-NBP treatment significantly increased the choline acetyltransferase activity and dose-dependently decreased the acetylcholinesterases activity in the hippocampus of aged rats. The immunohistological study demonstrated that expressions of β-secretase and hyperphosphorylated tau protein were significantly increased in the hippocampus CA1 subfield and parietal cortex in aged rats. However, they were decreased significantly by treatment of l-NBP and memantine for 3 months. Our results indicated that long-term treatment with l-NBP might prevent age-related neurodegenerative changes by modulation of cholinergic system, reduction of phosphorylated tau and maintain structure and morphology of neurons. Therefore, l-NBP might be a potential drug for treatment of senile dementia.     

Isolation of narciprimine from Cyrtanthus contractus (Amaryllidaceae) and evaluation of its acetylcholinesterase inhibitory activity

Ethnopharmacological relevance

Plants of the family Amaryllidaceae are used widely in traditional medicine in South Africa. Several of these, including representatives of the genus Cyrtanthus find use in the treatment of mental illness and age-related dementia.

Aim of the study

Based on the distribution of central nervous system-activating alkaloidal constituents within the genus Cyrtanthus, Cyrtanthus contractus was here explored for such compounds which could interact with acetylcholinesterase (AChE), of significance in the progression of neurodegeneration associated with Alzheimer's disease.

Materials and methods

The known phenanthridone alkaloid narciprimine was isolated via column chromatography of the ethanolic extract of bulbs of Cyrtanthus contractus. The structure of the compound was determined by high field 2D NMR and mass spectroscopic techniques. The classical method of Ellman et al. was used in the determination of AChE inhibitory activity.

Results

The isolation of narciprimine from Cyrtanthus contractus is a landmark find since it has previously only been identified in Zephyranthes, Narcissus and Lycoris, genera endemic to the Americas, Europe and Asia, respectively. Narciprimine exhibited micromolar inhibitory activity (IC₅₀ 78.9) against the enzyme acetylcholinesterase.

Conclusion

This work represents the first isolation of narciprimine from an African Amaryllidaceae species, which may be of chemotaxonomic significance. The AChE inhibitory activity of narciprimine, taken together with activities of other structurally similar inhibitors within the series affords further insight to the structural details of the lycorine alkaloid acetylcholinesterase inhibitory pharmacophore.     

Galantamine administration reduces reactive astrogliosis and upregulates the anti-oxidant enzyme catalase in rats submitted to neonatal hypoxia ischemia

Neonatal hypoxia ischemia (HI) plays a role in the etiology of several neurological pathologies and causes severe sequelae. Acetylcholine is a neurotransmitter in the central nervous system and cholinesterase inhibitors have demonstrated a positive action over HI induced deficits. In order to evaluate the effects of pre and post-hypoxia administrations of galantamine, a cholinesterase inhibitor, in a model of perinatal HI, Wistar rats in the post-natal day 7 (PND7) were subjected to a combination of unilateral occlusion of the right carotid artery with the exposure to a 1 h hypoxia. Intraperitoneal injections of galantamine were administered in two different protocols: one pre and other post-hypoxia. The analysis of brain structures volume at PND45 showed that pre-hypoxia galantamine treatment prevented tissue injury to the ipsilesional hippocampus. Also, immunofluorescence showed HI-induced increase in the number of astrocytes that was prevented by pre-hypoxia treatment. Biochemical analysis was performed in the ipsilesional hippocampus at PND8 and revealed that pre-hypoxia galantamine treatment: 1) prevented the neuronal loss induced by HI; 2) reduced the HI-induced hypertrophy of astrocytes; and 3) caused an increase in the activity of the anti-oxidant enzyme catalase. Overall, treatment with galantamine was able to prevent the brain damage, increase the survival of neurons, reduce astrocytic reaction and increase the activity of the anti-oxidant enzyme catalase in rats submitted to neonatal hypoxia ischemia.     

Role of acetylcholinesterase in the development of axon tracts within the embryonic vertebrate brain

In the developing vertebrate brain, acetylcholinesterase (AChE) expression coincides temporally with axon tract formation. Although AChE promotes neurite outgrowth in vitro, the role of this molecule in the development of axon tracts in vivo is unknown. To address this question, we examined the effects of the AChE inhibitor, BW284C51, on the formation of the early scaffold of axon tracts in the embryonic Xenopus brain. In exposed Xenopus brain preparations, axons elongate and establish a normal topography of axon tracts. However, when brains were exposed to BW284C51, the thickness of the major longitudinal axon tract, the tract of the post-optic commissure decreased in a dose-dependent manner. When BW284C51 was removed from the culture media axon tract development returned to normal within 5 h. These findings provide the first evidence for a non-classical role of AChE in the initial formation of axon tracts within the developing vertebrate brain.