Synthesis, cholinesterase inhibition and hepatotoxicity of tacrine-phenol-bifendate hybrids / 药学学报

A series of tacrine-phenol-bifendate hybrids (7a-7e, 8a-8e) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs) with low hepatotoxicity. All the compounds had potent ChEs inhibitory activity with half-inhibitory concentration (IC50) values at the nanomolar range. Compound 8d exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC50 value of 156.39 nmol·L-1 and compound 7b showed the most potent inhibition for butyrylcholinesterase with IC50 value of 16.33 nmol·L-1. Kinetic and molecular modeling studies showed that 8d targeted both the catalytic active site and the peripheral anionic site of AChE. In addition, these compounds showed low toxicity to hepatocytes, and compound 8d did not increase the level of reactive oxygen species in HepG2 cells.

Neuroprotective effects of bis(7)-tacrine in rat model with glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To assess the neuroprotective effect of bis(7)-tacrine in experimental Sprague-Dawley(SD)rat glaucoma.<p>METHODS: Totally 24 rats were randomly divided into control group, operated group, 0.5mg/kg bis(7)-tacrine group and 5mg/kg memantine group. Unilateral elevation of intraocular pressure(IOP)was produced by hypertonic saline injection into an episcleral vein. Animals were orally dosed daily with bis(7)-tacrine or memantine. IOP was measured in both eyes of animals per 3d, and the number of retinal ganglion cells and the thickness of nerve fiber layer axon bundle were measured at 5wk.<p>RESULTS: Elevated IOP were induced in 3 glaucoma groups. Compared with control group, the retinal ganglion cells decreased from 119.50±8.26 to 79.83±9.58 and the thickness of axon bundle come down from 13.40±0.60 μm to 6.64±0.50 μm in operated group. However the number of the retinal ganglion cells was 109.00±7.04 in bis(7)-tacrine group and 107.33±8.57 in memantine group individually. The thickness of axon bundle was 12.26±0.78μm in bis(7)-tacrine group and 10.13±1.19μm in memantine group individually.<p>CONCLUSION: Both bis(7)-tacrine and memantine inhibited retinal ganglion cells loss, but only bis(7)-tacrine decreased the thickness declining of axon bundle.

Neuroprotective effects of bis(7)-tacrine in rat model with glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To assess the neuroprotective effect of bis(7)-tacrine in experimental Sprague-Dawley(SD)rat glaucoma.<p>METHODS: Totally 24 rats were randomly divided into control group, operated group, 0.5mg/kg bis(7)-tacrine group and 5mg/kg memantine group. Unilateral elevation of intraocular pressure(IOP)was produced by hypertonic saline injection into an episcleral vein. Animals were orally dosed daily with bis(7)-tacrine or memantine. IOP was measured in both eyes of animals per 3d, and the number of retinal ganglion cells and the thickness of nerve fiber layer axon bundle were measured at 5wk.<p>RESULTS: Elevated IOP were induced in 3 glaucoma groups. Compared with control group, the retinal ganglion cells decreased from 119.50±8.26 to 79.83±9.58 and the thickness of axon bundle come down from 13.40±0.60 μm to 6.64±0.50 μm in operated group. However the number of the retinal ganglion cells was 109.00±7.04 in bis(7)-tacrine group and 107.33±8.57 in memantine group individually. The thickness of axon bundle was 12.26±0.78μm in bis(7)-tacrine group and 10.13±1.19μm in memantine group individually.<p>CONCLUSION: Both bis(7)-tacrine and memantine inhibited retinal ganglion cells loss, but only bis(7)-tacrine decreased the thickness declining of axon bundle.

Progress of multi-target directed drugs based on tacrine and donepezil in alzheimer′s disease / 中国药学杂志

Alzheimer′s disease (AD) is a progressive multifactorial neurodegenerative disorder in elder people. Currently, the pathogenesis of AD is unclear, and it is presently incurable. In view of the complex network pathological features of AD, a single small molecule compound that can act simultaneously with multiple targets, called multi-target directed ligands (MTDLs), is considered to be an effective therapeutic strategy at present. Here, we review highlights recent MTDLs approach based cholinesterase inhibitors, antioxidant, metal chelator and neuroprotectant in the novel drug candidate prototypes for the treatment of AD.

Protective Effects of Acanthoic Acid on Acute Liver Injury in Mice / 医药导报

Objective To study protective effects of acanthoic acid ( AA) against acute liver injury. Methods Sixty mice were randomly divided into six groups (n=10 each),including normal control group,model control group,positive control group (N-acetyl -L- cysteine,NAC,300 mg·kg-1),and AA at small (50 mg·kg-1),middle (100 mg·kg-1),and high (200 mg·kg-1 ) dose groups. Each group received respective treatment for 3 days and fasted for 16 h before the last dose. All animals except of the normal control group were treated with tacrine (35 mg·kg-1 ) 1 h after the treatments. Hepatic pathological and serum biochemical changes were observed. Results The high-dose of AA significantly reduced the levels of AST (143±46) U·L-1 ,ALT (32±9) U·L-1 ,LDH (1 218±312) U·L-1 ,MDA (3. 24±0. 48) μmol·g-1 ,and GSH (417±15) mg·g-1 compared with the model control group (P<0. 05 or P<0. 01). Liver injury was also ameliorated in AA high dose group.Conclusion AA has a protective effect on acute liver injury in mice.

Effects of White Radish (Raphanus sativus) Enzyme Extract on Hepatotoxicity

Raphanus sativus (Cruciferaceae), commonly known as radish is widely available throughout the world. From antiquity it has been used in folk medicine as a natural drug against many toxicants. The present study was designed to evaluate the hepatoprotective activity of radish (Raphanus sativus) enzyme extract (REE) in vitro and in vivo test. The IC50 values of REE in human liver derived HepG2 cells was over 5,000 microg/ml in tested maximum concentration. The effect of REE to protect tacrine-induced cytotoxicity in HepG2 cells was evaluated by MTT assay. REE showed their hepatoprotective activities on tacrine-induced cytotoxicity and the EC50 value was 1,250 microg/ml. Silymarin, an antihepatotoxic agent used as a positive control exhibited 59.7% hepatoprotective activitiy at 100 microg/ml. Moreover, we tested the effect of REE on carbon tetrachloride (CCl4)-induced liver toxicity in rats. REE at dose of 50 and 100 mg/kg and silymarin at dose of 50 mg/kg were orally administered to CCl4-treated rats. The results showed that REE and silymarin significantly reduced the elevated levels of serum enzyme markers induced by CCl4. The biochemical data were supported by evaluation with liver histopathology. These findings suggest that REE, can significantly diminish hepatic damage by toxic agent such as tacrine or CCl4.

Development of the multi-target-directed acetylcholinesterase inhibitors based on tacrine / 中国药理学通报

Acetylcholinesterase is an important target for anti-Alzheimer's disease now.Much attention has been paid to the development of tacrine dimeric or hybrid compounds.The design strategy is transforming merely interacting with the two binding sites of acetylcholinesterase to get more activity and selectivity into the multi-target-directed function for the treatment of Alzheimer's disease. Herein,the tacrine dimeric or hybrid compounds development and the prospect for the treatment of AD have been reviewed.

Influence of Tacrine on Catecholamine Secretion in the Perfused Rat Adrenal Gland

The present study was designed to clarify whether tacrine affects the release of catecholamines (CA) from the isolated perfused model of rat adrenal gland or not and to elucidate the mechanism of its action. Tacrine (3 X 10(-5)~3 X 10(-4) M) perfused into an adrenal vein for 60 min inhibited CA secretory responses evoked by ACh (5.32 X 10(-3) M), DMPP (a selective neuronal nicotinic agonist, 10(-4) M for 2 min) and McN-A-343 (a selective muscarinic M1-agonist, 10(-4) M for 2 min) in relatively dose- and time- dependent manners. However, tacrine failed to affect CA secretion by high K+ (5.6 X 10(-2) M). Tacrine itself at concentrations used in the present experiments did not also affect spontaneous CA output. Furthermore, in the presence of tacrine (10(-4) M), CA secretory responses evoked by Bay-K-8644 (an activator of L-type Ca2+ channels, 10(-4) M), but not by cyclopiazonic acid (an inhibitor of cytoplasmic Ca2+-ATPase, 10(-4) M), was relatively time-dependently attenuated. Also, physostigmine (10(-4) M), given into the adrenal gland for 60 min, depressed CA secretory responses evoked by ACh, McN-A-343 and DMPP while did not affect that evoked by high K+. Collectively, these results obtained from the present study demonstrate that tacrine greatly inhibits CA secretion from the perfused rat adrenal gland evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors, but does fail to affect that by direct membrane-depolarization. It is suggested that this inhibitory effect of tacrine may be exerted by blocking both the calcium influx into the rat adrenal medullary chromaffin cells without Ca2+ release from the cytoplasmic calcium store, that is relevant to the cholinergic blockade. Also, the mode of action between tacrine and physostigmine in rat adrenomedullary CA secretion seems to be similar.

Effect of Tetrahydro-9-Aminoacridine on Acetylcholine Release in the Rat Hippocampus / 대한정신약물학회지

It is well known that the cholinergic innervation of hippocampal formation plays an important role in the process of memory and learning, and the deficit of this system might be a cause of the senile dementia including Alzheimer's disease. Several studies have suggested that increased central cholinergic activity could improve the cognitive deficits of the senile dementia. Therefore, many attempts have been made to reverse theses cognitive impairment by enhancing the central cholinergic activity through the use of cholinomimetics such as ACh precusor, cholinesterase(ChE) inhibitors and direct cholinoceptor agonists. Since Summers et al. reported that tacrine is worthy of novice as a possible palliative treatment for Alzheimer's disease, it has been shown to improve the memory and cognitive functions in some patients. Although tacrine is a potent centrally cholinesterase inhibitor, it seems unlikely that this property alone could underlie its clinical effect. Because the eserine, a specific cholinesterase inhibitor, showed little improvement in such patients, it is possible that tacrine may act in a different way to produce its clinical efforts. There are reports that tacrine blocked the some types of cation channels and the muscarinic receptors, and stimulated the nicotinic receptors in the central nervous system. After all, though a large body of experimental data have been accumulated, the mechanism controlling ACh release be tacrine still remains to be elucidated. In attempt to address the abode issue, this study was designed to delineate the action mechanism of tacrine on the electrically-evoked ACh release in the rat hippocampus.