Cholinergic Blocker for Cognitive Impairment
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Vanderbilt University Medical Center
Disqualifiers: Stroke, Epilepsy, others
Trial Summary
What is the purpose of this trial?This study will use an anticholinergic pharmacological probe to examine attention network function in SCD using EEG. The overall hypothesis is that in older adults with SCD, normal cognitive performance is maintained by compensatory attention network activity, supported by enhanced cholinergic function. The investigators anticipate that SCD will be associated with greater compensatory attention network activity and that disrupting this compensatory process through anticholinergic challenge will result in a greater negative effect on attentional performance (Attention Network Test, ANT) and attention network functioning (EEG) in older adults with SCD compared to those without SCD.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Mecamylamine for cognitive impairment?
The research suggests that the cholinergic system, which Mecamylamine affects, plays a role in cognitive processes. However, studies show that blocking nicotinic receptors with Mecamylamine can lead to cognitive impairments, particularly in memory, which may not support its effectiveness for improving cognitive impairment.
12345Is the cholinergic blocker Mecamylamine safe for humans?
Mecamylamine has been studied for various conditions and is known to cause cognitive impairments, especially at higher doses, and older adults may be more sensitive to these effects. It can also cause side effects related to its action on the nervous system, but at lower doses, it has been used safely in research settings.
34678How does the drug differ from other treatments for cognitive impairment?
This drug is unique because it targets both muscarinic and nicotinic receptors, which are involved in memory and attention processes. By blocking these receptors, it may provide a more comprehensive approach to addressing cognitive impairments compared to treatments that target only one type of receptor.
23469Eligibility Criteria
This trial is for non-smoking adults aged 55 or older who have mild cognitive issues but are generally in good health. They should score above 25 on the MoCA test, indicating only slight memory concerns, and have a GDS rating below 3, showing minimal daily life impact.Inclusion Criteria
You do not smoke cigarettes or tobacco products.
You have a good score on a test called Montreal Cognitive Assessment (MoCA), which measures your memory and thinking skills, and your Global Deterioration Scale (GDS) rating shows that you have mild or no cognitive impairment.
I am 55 years old or older.
Exclusion Criteria
I have a primary neurological disorder like stroke or epilepsy.
I cannot take certain medications due to health risks.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants undergo anticholinergic or placebo challenge with cognitive testing and EEG sessions
1 day per visit, 2 visits total
2 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
1 week
Participant Groups
The study tests how an anticholinergic drug called Mecamylamine affects attention in aging individuals with slight cognitive decline. Participants will be compared to those taking a placebo while their brain activity and attention performance are monitored using EEG and specific tests.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Anticholinergic ChallengeExperimental Treatment1 Intervention
All participants will receive oral mecamylamine or IV scopolamine for 1 day
Group II: Placebo ChallengePlacebo Group1 Intervention
All participants will receive oral placebo for 1 day
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Vanderbilt University Medical CenterNashville, TN
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Who Is Running the Clinical Trial?
Vanderbilt University Medical CenterLead Sponsor
References
Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. [2013]Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimer's disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.
Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses. [2018]Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg i.v.), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone.
Cognitive performance and cholinergic transmission: influence of muscarinic and nicotinic receptor blockade. [2021]The cholinergic system is essential in mediating cognitive processes. Although there has been extensive research regarding cholinergic receptor subsystems, the specific contribution of the muscarinic and nicotinic receptor system to cognitive processes still has not been sufficiently explored. In the present study, we examined the selective contribution of muscarinic and nicotinic antagonism to cognitive performance in healthy human subjects. A single-blind, double-dummy, time-elapsed, repeated measures cross-over design was used on 15 healthy males. Subjects completed a neuropsychological test battery assessing a wide range of cognitive domains after 0.4 mg scopolamine (intravenous), 0.2 mg/kg mecamylamine (max. 15 mg; oral) or placebo. Subjects were tested under three conditions: placebo/placebo (PP), scopolamine/placebo (SP) and mecamylamine/placebo (MP). Results show that scopolamine significantly impaired the free recall and recognition performance in the verbal learning test. No other cognitive domain was affected, neither by scopolamine nor by mecamylamine. In line with the existing literature, antagonism of muscarinic receptors resulted in specific cognitive impairments, predominantly memory performance.
Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. [2015]Studies of the neurochemical pathology of Alzheimer's disease and Parkinson's disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with 10-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.
Modulation of arousal and sleep/wake architecture by M1 PAM VU0453595 across young and aged rodents and nonhuman primates. [2022]Degeneration of basal forebrain cholinergic circuitry represents an early event in the development of Alzheimer's disease (AD). These alterations in central cholinergic function are associated with disruptions in arousal, sleep/wake architecture, and cognition. Changes in sleep/wake architecture are also present in normal aging and may represent a significant risk factor for AD. M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs) have been reported to enhance cognition across preclinical species and may also provide beneficial effects for age- and/or neurodegenerative disease-related changes in arousal and sleep. In the present study, electroencephalography was conducted in young animals (mice, rats and nonhuman primates [NHPs]) and in aged mice to examine the effects of the selective M1 PAM VU0453595 in comparison with the acetylcholinesterase inhibitor donepezil, M1/M4 agonist xanomeline (in NHPs), and M1 PAM BQCA (in rats) on sleep/wake architecture and arousal. In young wildtype mice, rats, and NHPs, but not in M1 mAChR KO mice, VU0453595 produced dose-related increases in high frequency gamma power, a correlate of arousal and cognition enhancement, without altering duration of time across all sleep/wake stages. Effects of VU0453595 in NHPs were observed within a dose range that did not induce cholinergic-mediated adverse effects. In contrast, donepezil and xanomeline increased time awake in rodents and engendered dose-limiting adverse effects in NHPs. Finally, VU0453595 attenuated age-related decreases in REM sleep duration in aged wildtype mice. Development of M1 PAMs represents a viable strategy for attenuating age-related and dementia-related pathological disturbances of sleep and arousal.
Differential effects of scopolamine and mecamylamine on working and reference memory in the rat. [2019]The effects of the muscarinic antagonist scopolamine (0.1-0.6 mg/kg, IP) and the nicotinic antagonist mecamylamine (1-10 mg/kg) were compared in T-maze alternation and discrimination tasks in the rat. Scopolamine dose dependently disrupted performance on the alternation task and potentiated the increase in errors made in controls when the delay between forced and choice runs was increased from 0 to 30 s. Mecamylamine disrupted performance at the 10-mg/kg dose only and dose dependently inhibited the increase in errors made in controls when the delay between forced and choice runs was increased to 30 s. In simple T-maze discrimination, only the 0.6-mg/kg dose of scopolamine disrupted performance of the task, while mecamylamine at both 5 and 10 mg/kg disrupted task performance. These results confirm that working memory tasks are more sensitive to central muscarinic blockade than reference memory tasks. They also demonstrate that in delay conditions working memory performance is enhanced following central nicotinic blockade while reference memory performance is disrupted. This suggests that centrally active muscarinic and nicotinic antagonists have dissociable effects on memory processes in the rat.
Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders. [2013]Mecamylamine (Inversine), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 - 90 mg/day). However, more recent clinical studies suggest that mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because mecamylamine easily crosses the blood - brain barrier at relatively low doses (2.5 - 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed mecamylamine's hypothesized antidepressant activity and suggest that it may be effective as an augmentation pharmacotherapy for SSRI treatment resistant major depression. These areas of investigation for mecamylamine are reviewed and recommendations for future research directions are proposed.
Correlation of the amnestic effects of nicotinic antagonists with inhibition of regional brain acetylcholine synthesis in rats. [2015]Acetylcholine (ACh) is considered to play a primary role in normal mnemonic functioning. Although most research has centered on the central muscarinic cholinergic system, of recent interest in normal and pathologic cognitive processing is the role of the nicotinic cholinergic system. The purpose of this research was to further characterize the role of the nicotinic system in learning and memory processing in a classical passive avoidance task by rats. The centrally acting nicotinic antagonist mecamylamine produced a dose-dependent impairment of performance in the passive avoidance task, however, the peripherally acting nicotinic antagonist hexamethonium was ineffective in this test. To elucidate the potential neurochemical mechanisms underlying mecamylamine's amnestic effect, we examined the ability of the drug to alter specific dynamic components of rat brain cholinergic systems in five brain regions. Mecamylamine produced a dose-dependent inhibition of the synthesis of [3H]ACh from pulse-injected [3H]choline in all regions examined, but was without effect on endogenous, steady-state levels of ACh. As with the behavioral study, administration of hexamethonium was without effect on [3H]ACh synthesis. Calculation of the turnover rates of ACh allowed a correlation between the inhibition of the behavioral task and the inhibition of central cholinergic function. The high degree of correlation obtained (as well as earlier studies in nonhuman primates) underlined the possibility that presynaptically located nicotinic receptors on brain cholinergic neurons are tonically active and mediate a positive feedback mechanism for controlling cholinergic neuronal activity. These receptors may be the neurochemical substrate which underlie the behavioral changes after administration of nicotinic agonists and antagonists.
Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. [2019]Functional abnormalities in muscarinic and nicotinic receptors are associated with a number of disorders including Alzheimer's disease and schizophrenia. While the contribution of muscarinic receptors in modulating cognition is well established in humans, the effects of nicotinic receptors and the interactions and possible synergistic effects between muscarinic and nicotinic receptors have not been well characterized in humans. The current study examined the effects of selective and simultaneous muscarinic and nicotinic receptor antagonism on a range of cognitive processes. The study was a double-blind, placebo-controlled, repeated measures design in which 12 healthy, young volunteers completed cognitive testing under four acute treatment conditions: placebo (P); mecamylamine (15 mg) (M); scopolamine (0.4 mg i.m.) (S); mecamylamine (15 mg)/scopolamine (0.4 mg i.m.) (MS). Muscarinic receptor antagonism with scopolamine resulted in deficits in working memory, declarative memory, sustained visual attention and psychomotor speed. Nicotinic antagonism with mecamylamine had no effect on any of the cognitive processes examined. Simultaneous antagonism of both muscarinic and nicotinic receptors with mecamylamine and scopolamine impaired all cognitive processes impaired by scopolamine and produced greater deficits than either muscarinic or nicotinic blockade alone, particularly on working memory, visual attention and psychomotor speed. These findings suggest that muscarinic and nicotinic receptors may interact functionally to have synergistic effects particularly on working memory and attention and suggests that therapeutic strategies targeting both receptor systems may be useful in improving selective cognitive processes in a number of disorders.