Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope

Sonkusare, Swapnil K.; Kaul, Chandrika; Ramarao, P.

doi:10.1016/j.phrs.2004.05.005

Cited by 267 publications

(214 citation statements)

References 135 publications

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“…Startle testing began 210 min after pill administration, based on memantine pharmacokinetics in HS (Sonkusare et al, 2005), using a test session identical to that administered on the screening-day. During active and placebo drug tests, startle 'nonresponsiveness' was defined by a mean startle magnitude o10 units on pulse alone trials (Swerdlow et al, 2002a(Swerdlow et al, ,b, 2006a(Swerdlow et al, ,b, 2009(Swerdlow et al, , 2013.…”

Section: Cpd Subjectsmentioning

confidence: 99%

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Swerdlow

Bhakta

Chou

et al. 2015

Neuropsychopharmacol

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Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n = 84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

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Section: Cpd Subjectsmentioning

confidence: 99%

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Swerdlow

Bhakta

Chou

et al. 2015

Neuropsychopharmacol

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“…32 The precise mechanisms implicated in the pathogenesis of AD have not yet been fully elucidated; however, the neuronal loss via neuronal apoptosis, caused by various neurotoxins (e.g., glutamate and ␤-amyloid protein), seems to be the most fundamental reason underlying this disease. 14,33 Because apoptosis may be reversed only within a limited period of time, compounds that prevent apoptosis may have a therapeutic significance for AD. 34 Based on its special structure, bis(7)-Cognitin may possess multiple neuroprotective properties, which tacrine or other AChE inhibitors do not, or only weakly, possess.…”

Section: Multifunctional Potencies Of Bis(7)-cognitinmentioning

confidence: 99%

“…Furthermore, using fluorescence Ca 2ϩ imaging, patch-clamp and receptor-ligand binding techniques bis(7)-Cognitin was found to effectively buffer the intracellular Ca 2ϩ increase triggered by glutamate, to reduce NMDA-activated currents, and to compete with However, it has further been found that although bis(7)-Cognitin has a similar affinity and potency to memantine in blocking NMDAR, this dimer is much more potent than memantine in preventing glutamate-induced excitotoxicity in neurons. 14,37 Therefore, in addition to its blockade of NMDA receptors, the mechanisms of bis (7)-Cognitin against glutamate-induced excitoxicity were further probed. First, we demonstrated that NO mediated glutamate-induced excitotoxicity in primary cultured neurons.…”

Section: Prevention Of Excitotoxicity By Bis(7)-cognitin Via the Concmentioning

confidence: 99%

“…Therefore, this drug, which was approved in October 2003 by the U.S. Food and Drug Administration for treating AD, seems to be a new hope for treating moderate-to-severe AD patients. 14 In general, AChE inhibitors have limited success as they only improve memory in mild dementia, but cannot stop the process of neurodegeneration. The magnitude of response to AChE inhibitors depends on the integrity of presynaptic neurons.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

Mak

Jiang

et al. 2009

Neurotherapeutics

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Summary:Alzheimer's disease (AD) is a progressive and degenerative brain disorder that has emerged as one of the major public health problems in adults. Unfortunately, its molecular pathology and therapeutic strategies remain elusive. Because there are multiple factors closely indicated in the pathogenesis of AD, multiple drug therapy will be required to address the varied pathological aspects of this disease. Existing pharmacological approaches with one-molecule-one-target are limited in their ability to modify the pathology of AD. Novel therapeutics strategies comprise multifunctional compounds specifically designed to target concurrently on different sites at multifactorial etiopathogenesis of AD, thereby providing greater therapeutic efficacy. Over the past decade, our group has developed several series of dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and huperzine A, a unique anti-Alzheimer's drug originally discovered from a traditional Chinese medicinal plant. Bis(7)-Cognitin, one of our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and amyloid precursor protein/␤-amyloid cascade concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to arrest/modify pathological process of AD in addition to improving the cognitive functions for AD.

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“…Nicotinic acetylcholine receptors (nAchRs) and NMDA receptors (NMDARs) have been implicated in AD pathology, (D'Andrea and Nagele, 2006;Oddo and LaFerla, 2006;Sonkusare, et al, 2005). To test whether these receptors mediate the rapid effects of soluble Aβ on dendritic spines, we incubated hippocampal neurons for 2 hours with 7PA2-CM in the presence or absence of the noncompetitive NMDAR antagonists memantine (1μM) or MK801 (20μM), or the nAChR antagonist hexamethonium (C6; 100 μM).…”

Section: Achr and Nmdar Blockers Attenuate Aβ-induced Effects On Spinmentioning

confidence: 99%

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

Calabrese

Shaked

Tabarean

et al. 2007

Molecular and Cellular Neuroscience

119

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In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid β protein (Aβ), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 hours picomolar concentrations of cell-derived, soluble Aβ induce specific alterations in pre-and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Aβ within the first day reversed these spine changes. Further, spine changes reversed spontaneously by two days, because neurons acutely developed resistance to continuous Aβ exposure. Thus, rapid Aβ-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.

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Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope

Cited by 267 publications

References 135 publications

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

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