Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)

Abstract

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retrosplenial cortex (PC/RS) of rats after treatment with N-methyl-D-aspartate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investigate this, the present study examined the PC/RS cortex of male rats (age 60-70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous treatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (dizocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reticulum and perinuclear space. Ribosomal disaggregation and degranulation were also evident by 30 MPD. At all subsequent time points, dilatation of mitochondria and endoplasmic reticulum progressed in severity. Although the relative involvement of mitochondria and endoplasmic reticulum varied, glia were not involved. These ultrastructural data suggest that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible PC/RS cortical neurons. The early mitochondrial effects identified in this study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the relationship between the ability of certain NMDA antagonists to induce energy perturbations and neuronal vacuoles in the same region of the rat cerebral cortex.

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…We observed no neuronal vacuolization or other histopathological changes in the hippocampus, posterior cingulate and retrosplenial cortices at the light microscopy level after memantine administration as previously reported after the administration of NMDA antagonists (Fix et al, 1993(Fix et al, , 1994Creeley et al, 2008). However, our observation that chronic memantine administration was associated with axonal degeneration in the hippocampus may relate to other reported neurotoxic effects of NMDA antagonists (eg PCP, MK-801) (Low and Roland, 2004).…”

“…The selected coronal sections were cut at the level of the decussation of the corpus callosum (approximately À5.30 to À5.60 mm caudal to bregma) to ensure sampling each brain at the same rostrocaudal level. Also, the brain regions selected using this sampling scheme have been reported to be particularly vulnerable to vacuolization induced by the administration of NMDA antagonists (Fix et al, 1993(Fix et al, , 1994Creeley et al, 2008). A total of 10 neurons in each section of the posterior cingulate and retrosplenial cortices and the hippocampus were detected (under  100 objective lens) and evaluated for the presence and severity of interacytoplasmic vacuoles and other features of neuronal damage.…”

Effect of Berberine on Cell Survival in the Developing Rat Brain Damaged by MK-801

“…As described previously, we also observed changes of cell shape including intracytoplasmatic vacuoles in the cortex of rats treated with a low dose of MK-801 (0.5 mg/kg body weight) when stained with haematoxylin and eosin (Olney et al, 1989; Fix et al, 1994). We intraperitoneally injected 20 mg/kg of berberine, or vehicle, to the model animals for 5 days.…”

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

“…To ensure sampling of each brain at the same rostrocaudal level, we used coronal sections cut at a level where the decussation of the corpus callosum begins to vanish (approximately -5.30 to -5.60 mm caudal to bregma) [53]. We have determined in prior studies [15,16] that the vacuolar reaction following treatment with NMDA antagonist drugs is maximally severe at this rostrocaudal level. Bilateral counts of vacuolated neuronal profiles were performed on a representative section randomly selected from within the defined rostrocaudal level by an observer blind to the treatment conditions.…”