The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate

Ooigawa, Hidetoshi; Nawashiro, Hiroshi; Fukui, Shinji; Otani, Naoki; Osumi, Atsushi; Toyo’oka, Toshimasa; Shima, Katsuji

doi:10.1007/s00401-006-0108-2

Cited by 93 publications

(72 citation statements)

References 47 publications

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“…Dark neurons were Wrst noticed to occur in neurosurgical biopsies, but were not seen at autopsy. Because of their appearance after delayed Wxation or after mechanical trauma [23] to the brain prior to Wxation, a mechanical stress force [3] was hypothesized to produce dark neurons [4]. This explanation may appear cogent, since it is in accord with the appearance of dark neurons in neurosurgically obtained brain tissue, where biopsies are always subjected to mechanical forces prior to Wxation.…”

Section: Introductionmentioning

confidence: 68%

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Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex

Kherani

Auer

2008

Acta Neuropathol

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Dark neurons have plagued the interpretation of brain tissue sections, experimentally and clinically. Seen only when perturbed but living tissue is Wxed in aldehydes, their mechanism of production is unknown. Since dark neurons are seen in cortical biopsies, experimental ischemia, hypoglycemia, and epilepsy, we surmised that glutamate release and neuronal transmembrane ion Xuxes could be the perturbation leading to dark neuron formation while the Wxation process is underway. Accordingly, we excised biopsies of rat cortex to simulate neurosurgical production of dark neurons. To ascertain the role of glutamate, blockade of N-methyl-D-aspartate (NMDA) and non-NMDA receptors was done prior to formaldehyde Wxation. To assess the role of transmembrane sodium ion (and implicitly, water) Xuxes, tetraethylammonium (TEA) was used. Blockade of NMDA receptors with MK-801 and non-NMDA receptors with the quinoxalinediones (CNQX and NBQX) abolished dark neuron formation. More delayed exposure of the tissue to the antagonist, CNQX, by admixing it with the Wxative directly, allowed for some production of dark neurons. Aminophosphonoheptanoate (APH), perhaps due to its polarity, and TEA, did not prevent dark neurons, which were abundant in control formaldehyde Wxed material unexposed to either receptor or ion channelantagonists. The results demonstrate a role for the pharmacologic subtypes of glutamate receptors in the pathogenetic mechanism of dark neuron formation. Our results are consistent with the appearance of dark neurons in biopsy where the cerebral cortex has been undercut, and rendered locally ischemic and hypoglycemic, as well as in epilepsy, hypoglycemia, and ischemia, all of which lead to glutamate release. Rather than a pressure-derived mechanical origin, we suggest that depolarization, glutamate release or receptor activation are more likely mechanisms of dark neuron production.Keywords Dark neuron · Biopsy artifact · Histology · Excitatory amino acid receptor blocker · Pharmacology · NMDA receptor · APH · MK-801 · CNQX · NBQX · TEA

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Section: Introductionmentioning

confidence: 68%

“…Trauma is one of the many methods for experimentally producing dark neurons [23]. Simple trauma was originally proposed by Jan Cammermeyer as a physical or mechanical mechanism [3,4], presumably by causing expulsion of water from the neuron.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex

Kherani

Auer

2008

Acta Neuropathol

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“…Whether the dark appearance is the result of cytoskeletal protein contraction (actin) is still a source of debate. Some authors have postulated that this is a pressure-derived mechanical artifact of the unfixed brain (Cammermeyer, 1978;Ooigawa et al, 2006); others prevented it by blocking glutamate receptors, thus suggesting that dark neurons are induced by depolarization, glutamate release, and receptor activation (Kherani and Auer, 2008). Furthermore, since after cessation of the insult, many contracted 'dark' neurons revert to normal, it is advisable to be cautious about equating a darkly stained neuron with cell death (Auer et al, 1985).…”

Section: Light Microscopy and Macroscopymentioning

confidence: 99%

Visualizing Cell Death in Experimental Focal Cerebral Ischemia: Promises, Problems, and Perspectives

Zille

Farr

Przesdzing

et al. 2011

J Cereb Blood Flow Metab

121

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One of the hallmarks of stroke pathophysiology is the widespread death of many different types of brain cells. As our understanding of the complex disease that is stroke has grown, it is now generally accepted that various different mechanisms can result in cell damage and eventual death. A plethora of techniques is available to identify various pathological features of cell death in stroke; each has its own drawbacks and pitfalls, and most are unable to distinguish between different types of cell death, which partially explains the widespread misuse of many terms. The purpose of this review is to summarize the standard histopathological and immunohistochemical techniques used to identify various pathological features of stroke. We then discuss how these methods should be properly interpreted on the basis of what they are showing, as well as advantages and disadvantages that require consideration. As there is much interest in the visualization of stroke using noninvasive imaging strategies, we also specifically discuss how these techniques can be interpreted within the context of cell death.

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“…Sections were prepared at 46 days after injury. As previously described by Ooigawa et al (2006) we utilized a fluorescent Nissil stain (NeuroTRACE), to label both live and dead neurons in injured animals treated with saline or methamphetamine (Ooigawa et al, 2006). We found that treating rats with 0.500 mg/kg/h methamphetamine beginning at 8 or 12 h after severe TBI significantly reduced neuronal loss in the CA1 region of the hippocampus compared to injured, saline treated control animals (Fig.…”

Section: Methamphetamine Is Neuroprotective When Administration Is Dementioning

confidence: 93%

Preclinical and Clinical Development of Low Dose Methamphetamine for the Treatment of Traumatic Brain Injury

Poulsen¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEApril PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERUniversity of Montana 32 Campus Dr. Missoula, MT 59812 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis proposal addresses additional preclinical characterization of low dose methamphetamine as a neuroprotective agent for TBI. We have previously demonstrated that treatment with methamphetamine within 12 hours after TBI significantly improved cognition and functional behavior in 2-3 month old male Wistar rats. These studies were intended to examine the therapeutic effects of methamphetamine in female and aged male rats. We also repeated a MRI time course study with the intent of determining if there was a dose response effect associated with methamphetamine induced white matter track remodeling. We have determined that female rats represent a poor model for TBI. Unlike humans, female rats have a 3-day estrous cycle. This means they are endogenously exposed to the neuroprotective effects of estrogen and progesterone before, during and after injury. This allows them to recover to near normal levels within a few weeks of after injury. In this context, it is not possible to observe any kind of drug effect on cognitive or behavioral outcomes. We have determined that methamphetamine does not exhibit a therapeutic effect in aged rats. A number of changes exist in aged rats that could account for this observation. First, they have reduced dopamine receptors. We have shown that methamphetamine-mediated neuroprotection is dependent, in part, on the activation of dopamine receptors. This reduction of dopamine receptors also contributes to a condition of chronic inflammation. We have shown that methamphetamine reduces neuroinlammatory signaling. Thus, the reduction of dopamine receptor mediated signaling could explain the loss of protectiv...

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The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate

Cited by 93 publications

References 47 publications

Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex

Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex

Visualizing Cell Death in Experimental Focal Cerebral Ischemia: Promises, Problems, and Perspectives

Preclinical and Clinical Development of Low Dose Methamphetamine for the Treatment of Traumatic Brain Injury

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