Long-acting Acetylcholinesterase Inhibitor Research Articles

PROTECTION FROM β-AMYLOID PEPTIDE TOXICITY IN A TRANSGENIC CAENORHABDITIS ELEGANS MODEL BY PHENSERINE, A LONG-ACTING ACETYLCHOLINESTERASE INHIBITOR AND NIGELLA SATIVA OIL, AN ALKALOID ANTIOXIDANT

PROTECTION FROM β-AMYLOID PEPTIDE TOXICITY IN A TRANSGENIC CAENORHABDITIS ELEGANS MODEL BY PHENSERINE, A LONG-ACTING ACETYLCHOLINESTERASE INHIBITOR AND NIGELLA SATIVA OIL, AN ALKALOID ANTIOXIDANT

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits.

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit.

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Phenserine, a novel acetylcholinesterase inhibitor, attenuates impaired learning of rats in a 14-unit T-maze induced by blockade of the N-methyl-D-aspartate receptor.

The present study evaluated the interaction of the glutamatergic and acetylcholinergic systems in memory formation, with an overall emphasis on developing multi-system approaches for treating age-related cognitive decline and Alzheimer' s disease. Specifically, we used a 14-unit T-maze to investigate whether phenserine (PHEN), a long-acting acetylcholinesterase inhibitor, could overcome a learning deficit in rats induced by the NMDA receptor antagonist, 3-(+/-) 2-carboxypiperzin-4-yl) propyl phosphonic acid (CPP). Prior to drug treatment, 3-month-old male Fischer-344 rats were trained to criterion (13 of 15 shock avoidances) in a straight runway. Twenty-four hours later, rats were given i.p. injections of saline (SAL), CPP (9 mg/kg) + SAL or CPP + PHEN (0.25, 0.5 or 0.75 mg/kg) and received 15 massed training trials in a 14-unit T-maze. CPP significantly increased the number of errors made in the maze relative to controls, and phenserine significantly reduced the number of errors made relative to rats receiving CPP only, with the lowest dose being the most effective. These results provide further support of phenserine's potent, cognitive-enhancing properties, and suggest that combined modulation of glutamatergic and acetylcholinergic systems may be of potential benefit in developing new pharmacotherapies for Alzheimer's disease and age-related cognitive decline.

Donepezil

Donepezil is a highly selective, long-acting acetylcholinesterase inhibitor which has been approved in numerous countries for the treatment of Alzheimer's disease. Donepezil increases the levels of acetylcholine in the brain of patients with Alzheimer's disease and presumably corrects some dysfunction associated with loss of cells in the basal forebrain. Several large-scale multinational clinical studies have demonstrated drug-related improvements in cognitive performance on objective psychometric tests and in ratings by clinicians of patients' function. Further studies will be needed to determine the long-term impact of donepezil on Alzheimer's disease and related dementias.

D-cycloserine attenuates scopolamine-induced learning and memory deficits in rats

The muscarinic antagonist scopolamine (SCOP; 1.0 mg/kg, ip) impaired both the acquisition of a learning task in the Morris water maze (MWM) and choice accuracy in the T-maze reinforced alternation procedure in rats. Acetylcholinesterase inhibitors (AChEIs) have been shown to attenuate these deficits. D-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, was investigated for its effects on SCOP-induced dementia in the MWM and T-maze paradigms. Combined administration of SCOP and DCS (3.0, 10.0, or 30.0 mg/kg, ip; 30 min pretreat) significantly reversed SCOP-induced deficits in the T-maze as measured by percentage correct choices. In addition, DCS (3.0 or 10.0 mg/kg, ip) significantly attenuated SCOP-induced deficits in the MWM as measured by latency to find the submerged platform. For comparison, the long-acting acetylcholinesterase inhibitor galanthamine (GAL) was tested in the T-maze (1.25, 2.5, or 5.0 mg/kg, ip) and the MWM (2.5 or 5.0 mg/kg, ip). GAL attenuated SCOP-induced deficits in both learning and memory models similar to DCS. These data suggest that the strychnine-insensitive partial glycine agonist, D-cycloserine, may be efficacious in disease states of central cholinergic hypofunction such as Alzheimer's disease.

The effects of acetylcholinesterase inhibitors on acetylcholinesterase in senile plaque: S. Nakamura, M. Yukawa and Y. Mimori. Third Dept of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minamiku, Hiroshima 734, Japan

As a long-acting acetylcholinesterase inhibitor (CI) with peripheral and central effects, tetrahydroaminoacridine (THA) has been extensively studied since 1981, for its potential efficacy as a symptomatic treatment for Alzheimer's disease (AD). This strategy is a part of an ongoing effort to bolster the basalis-neocortical and septo-hippocampal cholinergic systems that are severely altered in AD, using precursor loading (choline, lecithin), pre-synaptic releasing drugs (linopirdine, ondansetron), CI (physostigmine, HP-029, valnacrine, heptylphysostigmine, SDZ ENA 7 13), non-selective (arecoline, oxotremorine, bethanechol) and selective musarinic receptor agonists (LY 246708). To date, five major controlled clinical trials using THA have been published and are commented upon in terms of design, outcome variables, and toxicity. THA as a long-acting C1 has generated a lot of knowledge about drug testing in AD. Although the benefivrisk ratio is inadequate for marketing, future studies will have benefited from the THA experience. New regroupment of clinical investigators, such as the Consortium of Canadian Centres for Clinical Cognitive Research and the US Clinical Trials Consortium for AD is made possible to a great extent by the THA studies. Other CI is tested as symptomatic treatment for AD, but one must not forget that the ultimate goal is to understand the cause of AD, prevent it or at least delay its progression.

Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice

The effects of galanthamine, a long-acting acetylcholinesterase inhibitor, on passive avoidance and a modified Morris swim task were studied in mice. Lesions of the nucleus basalis magnocellularis (nBM) produced significant decreases in cortical choline acetyltransferase (ChAT) activity and profound deficits on the 24-h retention of a passive avoidance response and the reversal phase of the swim task. Galanthamine, administered 4 h before testing, improved performance of the two tasks in a dose-dependent fashion. In both tasks, galanthamine produced a U-shaped dose-response curve: the optimal dose was 3.0 mg/kg, IP on passive avoidance and 2.0 mg/kg on the swim task. The improvements in performance were not due to differences in motor activity or sensitivity to electric footshock. Behavioral tolerance did not occur from repeated doses of galanthamine; in fact, prior doses of galanthamine appeared to have a priming effect on later performance. In contrast to the effects in nBM-lesioned mice, galanthamine impaired performance of control mice on both tasks. Several characteristics of galanthamine suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease: 1) its ability to attenuate cognitive deficits in nBM-lesioned mice, 2) its relatively long half-life, and 3) its lack of tolerance effects in mice during 2 weeks of repeated dosing.