Identity of the dorsal hippocampal region most vulnerable to cerebral ischemia

doi:10.1016/0006-8993(93)91302-9

Brain Research

Volume 603, Issue 1, 12 February 1993, Pages 87-95

https://doi.org/10.1016/0006-8993(93)91302-9 Get rights and content

Abstract

Our previous investigations demonstrated that neurons in the area between the subiculum and the medial CA1 region and another area between the lateral CA1 and the CA3 region of the hippocampus are very vulnerable to cerebral ischemia in gerbils, where irreversible damages have been observed occur as early as 4–5 min after unilateral or bilateral common carotid artery occlusion. The present study was aimed to characterize these areas anatomically by using the immunohistochemical and zinc histochemical as well as Golgi silver impregnation methods. Our results indicated that these two areas which are topographically apart on the coronal section actually had a common origin in the rostral part of the hippocampus and that they were separated by insertion of the CA1 neurons between them in the more caudal part of the hippocampus. The distribution pattern of mossy fibers indicated that these areas belonged to the CA2 region. The double immunohistochemical and zinc histochemical procedure confirmed that these areas developed ischemic lesions promptly even without reperfusion but that the CA1 region did not develop similar lesions until after reperfusion for 12–24 h if the ischemic period was brief. While the reason for the observed susceptibility of the CA2 region is not certain at the present time, it is important to distinguish the ischemic lesions in the CA2 region from those in the CA1 and CA3 regions.

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Genomic approach to selective vulnerability of the hippocampus in brain ischemia-hypoxia
2015, Neuroscience
Citation Excerpt :
Given the difficulty to delineate CA2 in ischemic damage (Akai and Yanagihara, 1993) no specific discussion of CA2 will be provided in the remainder of the review. At the medial border of CA1, the transition of damage to the subiculum is not well studied (Akai and Yanagihara, 1993). Hilar neurons (“CA4”) are very vulnerable, and the somatostatin expressing subclass seems to be rapidly affected (Johansen et al., 1987).
Transient global ischemia selectively damages neurons in specific brain areas. A reproducible pattern of selective vulnerability is observed in the dorsal hippocampus of rodents where ischemic damage typically affects neurons in the CA1 area while sparing neurons in CA3 and granule cells. The “neuronal factors” underlying the differential vulnerability of CA1 versus CA3 have been of great interest. This review first provides on overview of the histological pattern of ischemic–hypoxic damage, the phenomenon of delayed neuronal death, the necrosis–apoptosis discussion, and multiple molecular mechanisms studied in the hippocampus. Subsequently, genomic studies of basal gene expression in CA1 and CA3 are summarized and changes in gene expression in response to global brain ischemia are surveyed. A formal analysis is presented for the overlap between genes expressed under basal conditions in the hippocampus and genes responding to ischemia–hypoxia in general. A possible role of the elusive vascular factors in selective vulnerability is reviewed, and a gene set for angiogenesis is then shown to be enriched in the CA3 gene set. A survey of selective vulnerability in the human hippocampus in relation to genomic studies in ischemia–hypoxia is presented, and neurodegeneration genes with high expression in CA1 are highlighted (e.g. WFS1). It is concluded that neuronal factors dominate the selective vulnerability of CA1 but that vascular factors also deserve more systematic studies.
PPAR-γ activator induces neuroprotection in hypercholesterolemic rats subjected to global cerebral ischemia/reperfusion injury: In vivo and in vitro inhibition of oxidative stress
2014, Experimental Gerontology
Citation Excerpt :
Global cerebral ischemia/reperfusion injury (GCI/R) occurs in conditions like cardiac arrest, coronary artery bypass surgery, cardio-respiratory failure, and others leading to drastic reduction of blood flow to the brain (Llinas et al., 2000). Global cerebral ischemia, for a short period of time, results in selective neuro-degeneration in vulnerable brain areas, such as CA1 region of the hippocampus (Akai and Yanagihara, 1993; Pulsinelli 1995). The underlying mechanisms of CA1 neuronal loss following GCI/R may involve reactive oxygen species (ROS), inflammation, and apoptosis (Ferrer and Plana, 2003; Wang et al., 2007).
Hypercholesterolemia (HC) and aging combine to increase the incidence of cerebrovascular disease through oxidative stress. Our investigation examined the effects of diet-induced hypercholesterolemia (2% for 8 weeks) on the extent of brain injury in response to global cerebral ischemia/reperfusion (GCI/R) and the neuroprotective potentials of rosiglitazone in relation to oxidative stress. HC exacerbated the decline in the brain levels of GSH and the increase in MPO, proinflammatory markers and hippocampal lesions in response to GCI/R. HC rats receiving rosiglitazone, PPAR-γ agonist, demonstrated preservation of cell viability of CA1 hippocampal region and attenuation of brain edema. They also showed elevated levels of GSH and low levels of the other parameters similar to non-HC rats subjected to GCI/R. In vitro, rosiglitazone dose-dependently inhibited ROS generation by neutrophils. The results suggest exacerbation of brain lesions by HC in response to GCI/R. The neuroprotective therapeutic potentials of rosiglitazone are comparable to non-HC animals. Mechanisms of protection are possibly due to anti-oxidant, anti-inflammatory effects and scavenging properties of rosiglitazone. These results add to the beneficial therapeutic effects of rosiglitazone and its significance for age-associated diseases including hypercholesterolemia.
Chronic estradiol treatment increases CA1 cell survival but does not improve visual or spatial recognition memory after global ischemia in middle-aged female rats
2009, Hormones and Behavior
Transient global ischemia induces selective, delayed neuronal death in the hippocampal CA1 and cognitive deficits. Physiological levels of 17β-estradiol ameliorate ischemia-induced neuronal death and cognitive impairments in young animals. In view of concerns regarding hormone therapy in postmenopausal women, we investigated whether chronic estradiol treatment initiated 14 days prior to ischemia attenuates ischemia-induced CA1 cell loss and impairments in visual and spatial memory, in ovariohysterectomized (OVX), middle-aged (9–11 months) female rats. To determine whether the duration of hormone withdrawal affects the efficacy of estradiol treatment, hormone treatment was initiated immediately (0 week), 1 week, or 8 weeks after OVX. Age-matched, OVX and gonadally intact females were studied at each OVX interval. Ischemia was induced 1 week after animals were pretested on a variety of behavioral tasks. Global ischemia produced significant neuronal loss in the CA1 and impaired performance on visual and spatial recognition. Chronic estradiol modestly but significantly increased the number of surviving CA1 neurons in animals at all OVX durations. However, in contrast with previous results in young females, estradiol did not preserve visual or spatial memory performance in middle-aged females. All animals displayed normal locomotion, spontaneous alternation and social preference, indicating the absence of global behavioral impairments. Therefore, the neuroprotective effects of estradiol are different in middle-aged than in young rats. These findings highlight the importance of using older animals in studies assessing potential treatments for focal and global ischemia.
Neuroprotective effect of melatonin on brain damage induced by acute global cerebral ischemia in cats
2001, Archives of Medical Research
Melatonin has been proposed as a neuroprotective agent on the basis of its ability to function as a free radical scavenger, provided that lipoperoxidation and other free radical damage induced by reactive oxygen species resulting from cerebral ischemia are relevant pathophysiologic processes of ischemic neuronal damage.
The effects of melatonin or vehicle on neurologic deficit scores (Todd scale; maximal deficit score = 100, daily during 7 days after the ischemic episode) and neuronal population of hippocampal CA1–CA4 fields (cresyl violet stain, at the eighth day after the ischemic episode) were evaluated in adult male cats subjected to a 15-min period of acute global cerebral ischemia induced by cardiorespiratory arrest, and in cats subjected to a sham procedure. Continuous intravenous (iv) administration of either melatonin 10 mg/kg/h in 10% ethanol in saline or the vehicle alone (3 mL/kg/h) for 6 h starting 30 min after the end of the period of global cerebral ischemia was used as treatment.
Global cerebral ischemia resulted in a severe loss of neurons in hippocampal CA1–CA4 fields (9, 13, 30 and 28% remaining neurons, respectively) of ischemic vehicle-treated cats in comparison with sham cats (100%). By contrast, remaining neurons in these regions were between 81 and 100% in the ischemic melatonin-treated cats, values that are nonsignificantly different as compared with sham cats. Values of remaining neurons in CA1–CA4 fields in ischemic melatonin-treated cats were significantly higher than those in ischemic vehicle-treated cats. Neurologic deficit scores in ischemic vehicle-treated cats (42–77 at day 1, 6–39 at day 7) were significantly higher than those in ischemic melatonin-treated cats (16–38 at day 1, 0–6 at day 7) on the days after the ischemic episode.
Overall, the results support the neuroprotective effect of melatonin against the neuronal cerebral damage induced by acute global cerebral ischemia.
Dna cleavage and proteolysis of microtubule-associated protein 2 after cerebral ischemia of different severity
1999, Neuroscience
We report temporal profiles of cytoplasmic proteolysis and genomic DNA cleavage after cerebral ischemia of different severity in gerbils. Global forebrain ischemia by bilateral common carotid artery occlusion for 5 min with reperfusion, severe unilateral hemispheric ischemia by unilateral common carotid artery occlusion for 30 min with reperfusion, and complete ischemia by decapitation were used. The hippocampus was examined for proteolysis by using immunohistochemistry for microtubule-associated protein 2, DNA cleavage by using in situ nick-end labelling, and nuclear morphology by Hematoxylin staining. During evolution of delayed neuronal death after transient forebrain ischemia, loss of the immunoreaction for microtubule-associated protein 2 occurred almost in parallel with DNA cleavage in the CA1 region. In contrast, disappearance of the immunoreaction for microtubule-associated protein 2 was much faster than genomic DNA cleavage after unilateral hemispheric ischemia and reperfusion. The microtubule-associated protein 2 immunoreactivity was completely lost before development of changes in nuclear morphology or DNA cleavage after complete ischemia.
The present study demonstrated the differences between necrosis and delayed neuronal death, but the nuclear morphology in the latter was not exactly the same as seen in apoptosis. Some elements of both necrotic and apoptotic machineries may work following transient ischemia, and the degree of ischemic insult may determine the character of cell death process.
Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: Implications for schizophrenia?
1998, Biological Psychiatry
Background: Intracerebroventricular (ICV) administration of kainic acid to rats produces limbic-cortical neuronal damage that has been compared to the neuropathology of schizophrenia.
Methods: Groups of adult rats were administered ICV kainic acid and then assessed for neuronal loss and the expression of proteins relevant to mechanisms of neuronal damage after one and fourteen days. Neuronal loss was assessed by two-dimensional cell counting and protein expression was assessed by immunohistochemistry.
Results: ICV kainic acid administration was associated with both immediate (day 1) and delayed (day 14) neuronal loss in the dorsal hippocampus. The immediate injury was largely limited to the CA3 hippocampal subfield, while the delayed injury included the CA1 subfield. Multiple mechanisms of cell death appeared to be involved in the delayed neuronal loss, as evidenced by changes in the expression of glutamate receptor subunits, heat shock protein and jun protein.
Conclusions: ICV kainic acid administration to adult rats produces progressive damage to limbic-cortical neurons, involving both fast and slow mechanisms of cell death. Given the evidence for clinical deterioration, cognitive deficits and hippocampal neuropathy in some cases of schizophrenia, this animal model may be relevant for hypotheses regarding mechanisms of neurodegeneration in that disorder.

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Identity of the dorsal hippocampal region most vulnerable to cerebral ischemia

Abstract

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Life Sci.

Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia

J. Cereb. Blood Flow Metab.

Regional accumulation of calcium in postischemic rat brain

J. Neurochem.

N-methyl-d-aspartate receptors mediate hypoxic neuronal injury in cortical culture

J. Pharmacol. Exp. Ther.

Quantitative autoradiographic distribution ofl-[3H] glutamate-binding sites in rat central nervous system

J. Neurosci.

Changes in extracellular activity in cerebral ischemia

J. Cereb. Blood Flow Metab.

Immunohistochemical investigation of ischemic and postischemic damage after bilateral carotid occlusion in gerbils

Stroke

Electronmicroscopical localization of zinc in hippocampal mossy fiber synapses by a modified sulfide silver procedure

Histochemie

Light microscopical mapping of the hippocampal region, the pyriform cortex and corticomedial amygdaloid nuclei of the rat with Timm's sulphide silver method

Z. Anat. Entwick. Gesch.

Relationship between calcium accumulation and recovery of cat brain after prolonged cerebral ischemia

J. Cereb. Blood Flow Metab.

Studies on the structure of cerebral cortex. II. Continuation of the study of the ammonic system

J. Psychol. Neurol. (Lpz)

Quantitative autoradiographic distribution ofl-[³H] glutamate-binding sites in rat central nervous system