Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors

In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.     

Design, synthesis and biological evaluation of new 2-benzoxazolinone derivatives as potential cholinesterase inhibitors for therapy of alzheimer's disease

Currently acetylcholinesterase inhibitor (AChEI) therapy is one of the most frequently used methods in the treatment of Alzheimer's disease; tacrine, donepezil, rivastygmine and galantamine are applied in different stages of AD. In the present study, we propose a new series of 2-benzoxazolinone derivatives as potential cholinesterase inhibitors. These compounds were synthesized by condensation of 6-chloro acetyl-2-benzoxa zolinone with the corresponding amine and evaluated as acetylcholinesterase inhibitors using the colorimetric Ellman's method. Selectivity and the IC50 values were determined for the received derivatives. All tested compounds exhibited the inhibitory activity towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 3e showed stronger activity than the standard tacrine, and compound 3a showed activity similar to that of tacrine for AChE. Compounds 3a, 3b, 3c, and 3e showed stronger activity than the standard donepezil towards the inhibition of BChE, and the compound 3e showed stronger activity than donepezil towards AChE.     

Cytotoxicity Study of Tacrine,Structurally and Pharmacologically Related Compounds Using Rat Hepatocytes

ABSTRACT

Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, as an indication of potential hepatotoxicity. However, acute and chronic studies with a limited number of animal models have not demonstrated hepatotoxicity. the present study compared the cytotoxicity in hepatocyte cultures of tacrine with structurally (proflavine and 9-aminoacndine) or pharmacologically similar compounds (physostigmine), as well as structurally modified tacrine to determine if there was a structure activity relationship with regards to toxicity. Cytotoxicity was assessed by determination of extra-and intracellular amounts of lactate dehydrogenase. Cytotoxicity was assessed after a four-hour exposure over a test compound concentration range of 0 to 3 mM. Concentration-dependent cytotoxicity occurred with tacrine and all structurally related compounds. Physostigmine which is pharmacologically similar, but structurally different, did not induce cytotoxicity. Cytotoxic potency did not appear to be related to acetylcholinesterase inhibitory activity, while compounds with acridine structures induced cytotoxicity. Thus, in this in vitro model, cytotoxicity appears to be related to structure and not pharmacological action. Results of this study indicate that compounds structurally related to tacrine are cytotoxic because of the heterocyclic ring structure. Neither unsaturation of an aromatic ring of the heterocyclic compound, amino substitution of the heterocyclic rings, N-hydroxylation of the amino group, nor ring hydroxylation dramatically alter cytotoxicity.     

Effects of puerarin on scopolamine-, mecamylamine-, p-chloroamphetamine- and dizocilpine-induced inhibitory avoidance performance impairment in rats

Puerarin at 10-50 mg/kg attenuated the mecamylamine- but not scopolamine-induced acquisition impairment of inhibitory avoidance performance in an inverse U-shape manner. p-Chloroamphetamine- and dizocilpine-induced acquisition impairment were reversed by puerarin at 25-50 mg/kg. Both piracetam, and tacrine attenuated impairment of inhibitory avoidance performance induced by all used drugs. Furthermore, puerarin, piracetam and tacrine alone did not alter step-through latency in the training trail but puerarin at 50 mg/kg and tacrine plus mecamylamine prolonged it in comparison with mecamylamine alone. From these results, we suggest that puerarin attenuated the deficits of inhibitory avoidance performance induced by mecamylamine, p-chloroamphetamine, and dizocilpine, the effects were related to increasing cholinergic activity via nicotinic but not muscarinic receptors, activating NMDA receptors, and decreasing serotonergic neuronal activity.     

New tacrine-hydrazinonicotinamide hybrids as acetylcholinesterase inhibitors of potential interest for the early diagnostics of Alzheimer's disease

The syntheses and the preliminary results of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by an affinity series of tacrine-hydrazinonicotinamide hybrids are described. These molecules were prepared by condensation of tacrine analogues with the hydrazine nicotinate moiety (HYNIC). Derivatives 6a and 6b showed lower activity than the model tacrine, while compounds 6c and 6d showed the strongest affinity to AChE. All the tested compounds exhibited lower affinity for BChE than tacrine. Alzheimer disease (AD) is characterised by a deficit of acetylcholinesterase, and these new compounds, as ligands for 99mTc complexes, are potential radiopharmaceuticals for an early diagnosis of Alzheimer's disease.     

Inhibitory effect of orally administered donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on cholinesterase activity in rats

Donepezil hydrochloride ((+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5, 6-dimethoxy-indan-1-one monohydrochloride: E2020: donepezil) is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The present experiments were designed to compare the inhibitory effects of orally administered donepezil and other cholinesterase inhibitors, tacrine (9-amino-1,2, 3,4-tetrahydroacridine hydrochloride), (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate (ENA-713, rivastigmine) and 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), on the cholinesterase activity in the brain and plasma of rats. Moreover, in order to validate the cholinesterase inhibition data, we measured the brain and plasma concentrations of these drugs. Oral administration of donepezil, tacrine, ENA-713 or TAK-147, caused a dose-dependent inhibition of brain and plasma cholinesterase activities. The ID(50) values of these compounds for brain cholinesterase activity were 6.3, 40.5, 7.2 and 26.8 micromol/kg, respectively. On the other hand, the ID(50)170, 9.7 and 51.2 micromol/kg, respectively. Thus, the ratios of the ID(50)4.2, 1.3 and 1.9, respectively. Brain and plasma concentrations of donepezil, tacrine and TAK-147 increased dose-dependently. The ratios of the concentrations (brain/plasma) of these compounds were 6.1-8.4 for donepezil, 14.5-54.6 for tacrine and 7.0-20.6 for TAK-147. The values of 50% inhibitory concentration of these drugs in the brain were 0.42, 3.5 and 1.1 nmol/g, respectively. In contrast, the brain and plasma concentrations of ENA-713 at all doses, except the two highest doses, were below the quantification limit. These results suggest that orally administered donepezil satisfactorily penetrates into the brain and inhibits cholinesterase there, and that donepezil is a potent and selective inhibitor of brain cholinesterase in comparison with plasma cholinesterase in vivo.     

Focal bicuculline increases extracellular dopamine concentration in the nucleus accumbens of freely moving rats as measured by in vivo microdialysis

Donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride)) is a centrally acting acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, its inhibitory effect on the activity of cholinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, heart, small intestine, liver and pectoral muscle of young adult as well as aged rats, in comparison with that of tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride). In aged animals, cholinesterase activity in heart, small intestine and pectoral muscle was lower, whereas that in plasma and liver was higher than in young rats. Both groups showed the highest levels in the brain. Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brain, plasma, erythrocyte, liver and pectoral muscle cholinesterase activity in young rats in a dose-dependent manner but had less effect on cholinesterase activity in heart and small intestine. In aged animals, inhibition of cholinesterase activity in the brain, erythrocytes and pectoral muscle by donepezil was more potent than that in young animals. Tacrine, at doses of 5, 10 and 20 mg/kg, p.o., dose-dependently inhibited cholinesterase activity in all tissues of both young and aged animals, but most potently in heart, small intestine and liver. The inhibition of cholinesterase activity by tacrine in the brain, plasma, erythrocytes, heart and liver was more potent in aged rats than in tissues of young rats. Brain and plasma concentrations of unchanged donepezil and tacrine were measured in the same animals as used for the cholinesterase inhibition study. Brain and plasma concentrations of donepezil and tacrine were higher in aged than in young animals. It is concluded that the inhibitory effects of donepezil and tacrine on cholinesterase activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animals. It is also suggested that the effect of donepezil on cholinesterase activity is more tissue-selective than that of tacrine.     

Tacrine-induced increase in the release of spontaneous high quantal content events in Torpedo electric organ.

1. The anticholinesterases, tacrine (100 microM) and physostigmine (60 microM) had different effects on the amplitude distribution and kinetics of miniature endplate currents (m.e.p.cs) recorded extracellularly from the electric organ of Torpedo marmorata. 2. Tacrine increased the ratio of giant miniatures (larger than 4 mV of amplitude) to more than 20% of recorded spontaneous events. In the presence of physostigmine such events represented only 4%. 3. Both tacrine and physostigmine increased the rise time and the decay phase of normal-sized m.e.p.cs when compared to control conditions. Both effects were significantly greater for tacrine. 4. We have tested the specificity of the tacrine effect on ectoenzyme activities associated with plasma membranes of these pure cholinergic nerve endings. Tacrine does not act unspecifically on every ectoenzyme, because it is not able to block the ectoapyrase activity even at a concentration 100 fold greater than that required to inhibit 94% of AChE. 5. We conclude that the differential effects of tacrine and physostigmine can be explained in terms of undetermined presynaptic actions of tacrine, while comparable effects of the two compounds can be explained through a shared anticholinesterase activity.     

Thieno[2,3-b]pyridine amines: Synthesis and evaluation of tacrine analogs against biological activities related to Alzheimer's disease

In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC₅₀ values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors ( 5e and 5d ) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (βA) aggregation and β-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.     

Prophylactic administration of non‐organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone

Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC‐induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)‐approved substance for such pre‐treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad‐spectrum alternatives, we have assessed in vivo the mortality‐reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K‐27), when given in equitoxic dosage (25% of LD₀₁) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre‐treatment. All tested AChE inhibitors reduced terbufos sulfone‐induced mortality significantly (p ≤ 0.05) as compared with the non‐treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone‐induced mortality was achieved, when K‐27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre‐treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K‐27) in case of imminent OPC exposure may be a viable option. Copyright © 2013 John Wiley & Sons, Ltd.     

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.     

Design and synthesis of thienopyridines as novel templates for acetylcholinesterase inhibitors

New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as a new drug candidate for the treatment of Alzheimer’s disease (AD) through the binding to both catalytic and peripheral sites of the enzyme. Therefore, a series of thienopyridine analogs of tacrine were synthesized and investigated for their ability to inhibit the activity of AChE in comparison with tacrine. All the compounds were found to inhibit AChE activity, especially compounds 7b and 11a, which were found to be more potent than tacrine.     

Research and development of donepezil hydrochloride,a new type of acetylcholinesterase inhibitor

A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.     

Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture

Extracts obtained by organic solvents from the root of Coptis teeta in Myanmar (Burma), were tested for growth inhibitory activity against Giardia lamblia, Trichomonas vaginalis and Entamoeba histolytica in axenic culture. All extracts had anti-protozoal activity with the methanol extract, in particular, being effective against all 3 parasites. By chromatographic analysis, the extracts were shown to contain berberine compounds and other alkaloids. Comparing the inhibitory effects of the methanol extract with berberine sulfate, a berberine salt previously shown to possess inhibitory activity, it was observed that the crude extract was more effective than the salt. This suggests that the greater inhibitory activity of the crude extract may be due to the cumulative contributions of its contained berberines and alkaloids. Based on these findings, it appears that the berberine compounds may be useful as chemotherapeutic agents against the 3 parasites tested.     

Tacrine is not an ideal probe drug for measuring CYP1A2 activity in vivo

AIMS: The aim of the present study was to examine the CYP1A2 substrate tacrine as a possible alternative to caffeine for assessing CYP1A2 activity in vivo. METHODS: Eighteen, healthy, nonsmoking men participated. Each volunteer was tested by caffeine (200 mg orally), and caffeine metabolic ratios were calculated. Subsequently, on two occasions, separated by at least 4 weeks, each volunteer was tested with tacrine (40 mg orally). The apparent oral clearance, partial clearances and different metabolic ratios of tacrine were determined. RESULTS: The median oral clearances of tacrine in the two study periods were 1893 l h-1 (range: 736-3098) and 1890 l h-1 (range: 438-4175), respectively. The interindividual coefficient of variation was 42% and 49%, respectively. The intraindividual coefficients of variation ranged from 0.28% to 64% (median: 13%). In both study periods, the oral clearance of tacrine correlated with the caffeine urinary metabolic ratio. However, only modest magnitudes of correlation were observed (rs: 0.64-0.66, P<0. 01). No tacrine metabolic ratio correlating with the oral clearance of tacrine was found. Conclusion The applicability of tacrine as a probe drug for measuring CYP1A2 activity in vivo appears limited.     

Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.     

First gallamine-tacrine hybrid: design and characterization at cholinesterases and the M2 muscarinic receptor

Gallamine and tacrine are allosteric antagonists at muscarinic M2 acetylcholine receptors and inhibitors of acetylcholinesterase. At both acetylcholine-binding proteins, gallamine and tacrine are known to occupy two different binding sites: in M2 receptors within the allosteric binding area and in acetylcholinesterase at its catalytic and its peripheral site. To find new ligands of both targets, we designed a gallamine-tacrine dimer and several derived hybrid compounds to address the two binding sites. Their M2 receptor allosteric and acetylcholinesterase inhibitory potential was determined. The hybrid compounds revealed an allosteric potency in the low nanomolar range exceeding the allosteric potency of gallamine and tacrine by factors of 100 and 4800, respectively. Cholinesterase inhibition was augmented by hybrid formation, and all compounds exhibited IC50 values in the lower nanomolar range. Thus, gallamine-tacrine hybrid formation is a valuable approach toward high affinity ligands concurrently targeting these acetylcholine-binding proteins.     

Recent developments in the synthesis of acetylcholinesterase inhibitors

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedl?nder condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.     

Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum.

1. The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [3H]-dopamine. In this preparation, nicotinic cholinoceptor activation evoked [3H]-dopamine release. 2. Antagonist activity was examined by giving a brief nicotine (1 microM) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3-300 microM). Physostigmine, neostigmine and tacrine produced a concentration-dependent blockade. Physostigmine and tacrine were particularly potent (IC50S approx. 10 microM and 1 microM, respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 microM). 3. Nicotinic blockade produced by superfusion with physostigmine (30 microM) was insurmountable when tested against nicotine (0.1-100 microM). 4. Physostigmine (30 microM) also reduced responses to the nicotinic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K+ or (+)-amphetamine. A higher concentration of physostigmine (300 microM) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K+. Tacrine (3 microM) reduced responses to nicotine and to high K+ but did not affect responses to amphetamine. 5. Physostigmine (0.3-300 microM), given as a brief pulse, did not produce a nicotinic agonist-like effect. 6. Physostigmine, neostigmine, tacrine and DFP (all at 30 microM) each produced near-total (> 96%) inhibition of AChE activity. However, DFP at a concentration (60 microM) that produced a degree of AChE inhibition equal to that of physostigmine 30 microM, did not significantly reduce nicotine-induced dopamine release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ferulic acid on the impairment of inhibitory avoidance performance in rats

Ferulic acid (50 and 100 mg/kg) reversed the step-through latency shortened by scopolamine and cycloheximide but not by p-chloroamphetamine in an inhibitory avoidance performance. Piracetam and tacrine might reverse the step-through latency shortened by the above drugs. However, ferulic acid, piracetam or tacrine alone at any used dose did not influence motor activity produced by non-shock rats. Furthermore, the cerebral blood flow of rats treated with ferulic acid, piracetam or tacrine was enhanced. From these results, we suggest that the potency of ferulic acid was better than that of piracetam, but its action mechanism was somewhat different from that of piracetam and tacrine. Thus, the attenuating effects of ferulic acid on the avoidance performance impairment were related to memory processes, and might be enhancing the cholinergic activities and cerebral blood circle.