PMID- 10869841
OWN - NLM
STAT- MEDLINE
DCOM- 20000821
LR  - 20190712
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 98
IP  - 3
DP  - 2000
TI  - Benzodiazepines protect hippocampal neurons from degeneration after transient 
      cerebral ischemia: an ultrastructural study.
PG  - 471-84
AB  - The ability of full and partial benzodiazepine receptor agonists to prevent DNA 
      fragmentation and neuronal death after transient cerebral ischemia was 
      investigated in the Mongolian gerbil. Diazepam (10mg/kg, i.p.) or the partial 
      agonist imidazenil (3mg/kg, i.p.) was administered 30 and 90min after transient 
      forebrain ischemia produced by occlusion of the carotid arteries for 5min. 
      Treatment with diazepam completely protected CA1b hippocampal pyramidal neurons 
      in 94% of the animals and partially protected pyramidal neurons in 6% of the 
      animals, as assessed with a standard Nissl stain three and four days after 
      ischemia. DNA fragmentation was examined by the terminal dUTP nick-end labeling 
      (TUNEL) reaction. Prior to cell death, there were no TUNEL-positive neurons in 
      area CA1b. By three days after ischemia, when neuronal degeneration was nearly 
      complete, 14 out of 16 gerbils exhibited a positive TUNEL reaction throughout 
      area CA1b stratum pyramidale. In 13 out of 14 gerbils treated with diazepam, no 
      TUNEL-positive neurons were observed in this region. Imidazenil was less 
      effective than diazepam with respect to both neuroprotection and prevention of 
      DNA fragmentation. Three days after ischemia, six out of eight gerbils treated 
      with imidazenil showed partial to complete neuroprotection. Imidazenil completely 
      prevented DNA fragmentation in only one of the animals; varying degrees of TUNEL 
      reaction persisted in the remainder. To determine whether the neurons protected 
      by diazepam had a normal ultrastructure, gerbils were killed two to 30 days after 
      ischemia and the hippocampal neurons in area CA1b were examined by electron 
      microscopy. Within the first 48h after ischemia, early cytoplasmic changes of 
      varying degrees (e.g., vacuolation, rough endoplasmic reticulum stacking, swollen 
      mitochondria) and electron-dense dendrites were observed in gerbils not treated 
      with diazepam. Degeneration was nearly complete by three days after ischemia. In 
      contrast, pyramidal neuron ultrastructure appeared normal in gerbils that 
      exhibited complete area CA1b neuroprotection (defined at the light microscope 
      level) by diazepam when studied two, seven or 30 days after ischemia. In gerbils 
      with partial protection of area CA1b, most of the remaining neurons exhibited 
      varying degrees of necrosis when studied 30 days after ischemia. No apoptotic 
      bodies were observed. We conclude that: (i) diazepam can fully protect CA1 
      pyramidal cells from the toxic effects of transient cerebral ischemia; (ii) when 
      diazepam affords only partial neuroprotection, the residual CA1 pyramidal cells 
      exhibit ultrastructural abnormalities consistent with necrotic damage; and (iii) 
      diazepam is a more efficacious neuroprotectant than the partial benzodiazepine 
      receptor agonist, imidazenil.
FAU - Schwartz-Bloom, R D
AU  - Schwartz-Bloom RD
AD  - Department of Pharmacology and Cancer Biology, Duke University Medical Center, 
      Box 3813, Durham, NC 27710, USA. schwa001@duke.edu
FAU - Miller, K A
AU  - Miller KA
FAU - Evenson, D A
AU  - Evenson DA
FAU - Crain, B J
AU  - Crain BJ
FAU - Nadler, J V
AU  - Nadler JV
LA  - eng
GR  - NS06233/NS/NINDS NIH HHS/United States
GR  - NS28791/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (GABA Modulators)
RN  - 0 (Imidazoles)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, GABA-A)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 7N95V6864R (imidazenil)
RN  - Q3JTX2Q7TU (Diazepam)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Benzodiazepines/pharmacology
MH  - DNA Fragmentation
MH  - Diazepam/*pharmacology
MH  - GABA Modulators/*pharmacology
MH  - Gerbillinae
MH  - Imidazoles/pharmacology
MH  - In Situ Nick-End Labeling
MH  - Ischemic Attack, Transient/*drug therapy/pathology
MH  - Male
MH  - Microscopy, Electron
MH  - Nerve Degeneration/*drug therapy/prevention & control
MH  - Neuroprotective Agents/*pharmacology
MH  - Pyramidal Cells/chemistry/cytology/ultrastructure
MH  - Receptors, GABA-A/physiology
EDAT- 2000/06/28 11:00
MHDA- 2000/08/29 11:01
CRDT- 2000/06/28 11:00
PHST- 2000/06/28 11:00 [pubmed]
PHST- 2000/08/29 11:01 [medline]
PHST- 2000/06/28 11:00 [entrez]
AID - S0306-4522(00)00144-5 [pii]
AID - 10.1016/s0306-4522(00)00144-5 [doi]
PST - ppublish
SO  - Neuroscience. 2000;98(3):471-84. doi: 10.1016/s0306-4522(00)00144-5.