TY - JOUR
T1 - Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801
T2 - Potential relevance to Alzheimer's disease
AU - Wozniak, D. F.
AU - Dikranian, K.
AU - Ishimaru, M. J.
AU - Nardi, A.
AU - Corso, T. D.
AU - Tenkova, T.
AU - Olney, J. W.
AU - Fix, A. S.
N1 - Funding Information:
This study was supported in part by NIMH Research Scientist Award MH 38894 (J.W.O.), NIA Grant AG11355, and NIDA Grant DA 05072.
PY - 1998/11
Y1 - 1998/11
N2 - Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors by MK-801 induces neuronal degeneration in the posterior cingulate/retrosplenial cortex and other corticolimbic regions although damage in the latter has not been adequately characterized. This disseminated corticolimbic damage is of interest since NMDA hypofunction, the mechanism that triggers this neurodegenerative syndrome, has been postulated to play a role in the pathophysiology of Alzheimer's disease (AD). Several histological methods, including electron microscopy, were used to evaluate the neurotoxic changes in various corticolimbic regions of rat brain following MK-801 or a combination of MK-801 plus pilocarpine. We found that MK-801 triggers neuronal degeneration in a widespread pattern similar to that induced by phencyclidine and that females showed more damage than males. The neurotoxic reaction involved additional brain regions when muscarinic receptors were hyperactivated by administering pilocarpine with MK-801. Ultrastructural evaluation revealed that a major feature of the neurotoxic action involves degeneration of dendritic spines which entails loss of synaptic complexes. The ultrastructural appearance of degenerating neurons was generally inconsistent with an apoptotic mechanism, although evidence equivocally consistent with apoptosis was observed in some instances. The cell death process evolved relatively slowly and was still ongoing 7 days posttreatment. Relevance of these results to AD is discussed.
AB - Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors by MK-801 induces neuronal degeneration in the posterior cingulate/retrosplenial cortex and other corticolimbic regions although damage in the latter has not been adequately characterized. This disseminated corticolimbic damage is of interest since NMDA hypofunction, the mechanism that triggers this neurodegenerative syndrome, has been postulated to play a role in the pathophysiology of Alzheimer's disease (AD). Several histological methods, including electron microscopy, were used to evaluate the neurotoxic changes in various corticolimbic regions of rat brain following MK-801 or a combination of MK-801 plus pilocarpine. We found that MK-801 triggers neuronal degeneration in a widespread pattern similar to that induced by phencyclidine and that females showed more damage than males. The neurotoxic reaction involved additional brain regions when muscarinic receptors were hyperactivated by administering pilocarpine with MK-801. Ultrastructural evaluation revealed that a major feature of the neurotoxic action involves degeneration of dendritic spines which entails loss of synaptic complexes. The ultrastructural appearance of degenerating neurons was generally inconsistent with an apoptotic mechanism, although evidence equivocally consistent with apoptosis was observed in some instances. The cell death process evolved relatively slowly and was still ongoing 7 days posttreatment. Relevance of these results to AD is discussed.
UR - http://www.scopus.com/inward/record.url?scp=0032443119&partnerID=8YFLogxK
U2 - 10.1006/nbdi.1998.0206
DO - 10.1006/nbdi.1998.0206
M3 - Article
C2 - 10069574
AN - SCOPUS:0032443119
SN - 0969-9961
VL - 5
SP - 305
EP - 322
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 5
ER -