Quantitative analysis of factors influencing neuronal necrosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex

Fix, Andrew S.; Wozniak, David F.; Truex, Lewis L.; McEwen, Melanie L.; Miller, J. Philip; Olney, John W.

doi:10.1016/0006-8993(95)00842-e

Cited by 90 publications

(72 citation statements)

References 37 publications

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“…Harlan Sprague-Dawley female retired breeders (6 to 8 months old) were used because sensitivity to the neurotoxic effects of NMDA antagonists is influenced both by age and gender -female and fully adult rats are more sensitive than male or immature rats [14,17,28,49]. Memantine hydrochloride and 9-Amino-1,2,3,4-tetrahydroacridine (tacrine) were purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Animals and Drugsmentioning

confidence: 99%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg ip), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5 to 10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

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Section: Animals and Drugsmentioning

confidence: 99%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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“…In adult humans they trigger psychosis, [1][2][3][4][5][6][7][8][9][10] and in adult rats they produce neurotoxicity. [11][12][13][14][15][16][17][18][19][20][21] Developing methods for controlling or preventing these adverse reactions is an important goal, as it may permit the therapeutic potential of these agents to be realized.…”

Section: Introductionmentioning

confidence: 99%

“…Changes induced by a low dose of an NMDA antagonist are reversible, are regionally selective for neurons in the retrosplenial cortex (RSC 32 ), and consist of vacuolar changes in mitochondria and endoplasmic reticulum. 11 A high dose, or more prolonged treatment, triggers irreversible neurodegeneration affecting neurons not only in RSC, [12][13][14][15][16] but also in several other cerebrocortical and limbic brain regions. [17][18][19]21 After finding in early experiments, that two classes of drugs-GABA A agonists and muscarinic cholinergic antagonists-were effective in blocking the reversible neurotoxic reaction, we proposed ( Figure 1) that the mechanism involves loss of GABAergic inhibitory control over excitatory cholinergic neurons that innervate RSC neurons, with excessive cholinergic stimulation of RSC neurons being the proximal mechanism of neuronal injury.…”

Section: Introductionmentioning

confidence: 99%

Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

et al. 2002

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NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (eg antimuscarinics, non-NMDA glutamate antagonists, and ␣ 2 adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an ␣ 2 adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m 3 ) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.

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“…Cholinergic neurons in the cingulate cortex are likely to be innervated by projections from basal forebrain and glutamatergic neurons in the anterior thalamus. With less inhibitory (GABA) influence on these excitatory neurons, an increase in excitatory transmission would be expected in regions such as the posterior cingulate and retrosplenial cortexes (Fix et al 1995;Olney and Farber 1995b).…”

Section: Discussionmentioning

confidence: 99%