Biomedical subjects

Y Hakamata

Publications and source records attributed to Y Hakamata.

At least 19 recordsLinked to original sources

PubMed2005

Bone marrow cells differentiate into wound myofibroblasts and accelerate the healing of wounds with exposed bones when combined with an occlusive dressing.

BACKGROUND: The usefulness of bone marrow cells in accelerating wound healing has not been evaluated despite increasing evidence that bone marrow contains mesenchymal stem cells that have multipotentiality to differentiate into various types of cells after they enter the microenvironment of a specific tissue (niche). OBJECTIVES: To determine the effects of bone marrow cells and occlusive dressings in promoting wound healing in rats. METHODS: We investigated by grafting, biopsy and immunohistochemistry whether various types of cells derived from green fluorescent protein (GFP)-transgenic rats would differentiate into wound component cells when administered topically on the wounds of rats. We also investigated whether topical application of bone marrow cells with an occlusive dressing would accelerate the healing of wounds with exposed bones, as measured by planimetry. RESULTS: GFP-labelled bone marrow cells contained multipotent stem cells that sufficiently differentiated into wound myofibroblasts presenting with alpha-smooth muscle actin in granulation tissue. Other types of cells, including myocytes, adipocytes, peripheral blood cells from buffy coat and dermal fibroblasts, did not express myofibroblast characteristics morphologically or immunohistochemically. Application of bone marrow cells and an occlusive dressing accelerated the repair of wounds with exposed bones, compared with an occlusive dressing only or with the topical administration of bone marrow cells plus a semidry to dry dressing. CONCLUSIONS: Our study indicates that bone marrow cells accelerate the healing of wounds at least in part through their differentiation into wound myofibroblasts. Thus, treatment of wounds with bone marrow cells and a supportive occlusive dressing is effective in promoting the formation of healthy granulation tissue and also for the preparation of an ideal wound bed.

Animals↗

PubMed2004

Chronopharmacological studies of ketamine in normal and NMDA epsilon1 receptor knockout mice.

BACKGROUND: The effectiveness and toxicity of many drugs depends on the dosing-time schedule, relative to the circadian rhythms of biochemical, physiological, and behavioural processes. Previous studies have found chronopharmacology of ketamine, which is a N-methyl-d-aspartate (NMDA) receptor antagonist. The in vivo contribution of the NMDA receptor epsilon1 subunit (NR2A) in this effect is unclear. METHODS: In the present study, daily variations in the hypnotic effect of ketamine were determined in wild-type mice and NMDA epsilon1 knockout (KO) mice. RESULTS: The effect of ketamine had a definite daily variation in wild-type mice. No significant difference in blood concentration was observed at different dosing times (10:00 and 22:00). In NMDA receptor epsilon1 KO mice, the hypnotic effect of ketamine was weaker than in wild-type mice and there was no dependence on the time of administration. Significant pharmacokinetic differences were not observed between wild-type and KO mice. CONCLUSIONS: The enhanced hypnotic effect in the active phase of the circadian cycle is likely a result of changes with the time of day in the susceptibility of the central nervous system to ketamine. Knockout of the NMDA receptor epsilon1 subunit gene markedly reduced the effect of ketamine, and eliminated the time-dependent sensitivity to ketamine.

Anesthetics, Dissociative↗

PubMed2004

Characterization of hair follicles induced in implanted, cultured rat keratinocyte sheets.

Cultured rat keratinocyte sheets form hair follicles in combination with rat vibrissa dermal papillae when they are transplanted subcutaneously in syngeneic rats and athymic mice. In the present study, the histologic details of these induced follicles were analyzed by preparing cultured sheets mixed with normal rat keratinocytes and green fluorescent protein (GFP)-transgenic rat keratinocytes. Histologic examination demonstrated that some induced follicles maintained their size and morphology for at least 18 weeks, whereas others decreased in size and others totally differentiated into cornified structures between 3 and 6 weeks. The percentage of the grafts with GFP-positive cells decreased during the same period. This finding suggests that some GFP-positive cells were transient-amplifying cells that turned into terminally differentiated cells and were lost during this period. Some large follicles and some small follicles maintained their hair-producing ability and the proliferative activity in their hair matrix for 18 weeks. In addition, one 6-week-old follicle contained label-retaining cells in the outer root sheath. Seven of 25 follicles induced from chimera epithelium contained both GFP-positive cells and GFP-negative cells. These results suggest that stem cells are present in the induced follicle and the induced follicle consists of polyclonally derived cells. The presence of early anagen-like large follicles at week 6 and 9 and a telogen-like small follicle at week 18 also suggests that hair-growth cycle phases proceeded in the induced follicles. In conclusion, the follicles induced in the cultured keratinocyte sheets maintained hair-producing ability and proliferative activity for at least 18 weeks. This and the presence of label-retaining cells suggest that there are stem cells in the induced follicles, which seem to have a hair-growth cycle.

Animals↗

PubMed2004

Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A.

Inhibitory antibody formation is the most serious complication of factor (F)VIII replacement therapy in hemophilia A patients. FVIII-deficient mice were used to study new approaches for induction of immune tolerance. Neither antiFVIII inhibitory antibodies nor antiFVIII IgGs were observed in 13 of 14 adult mice that received 0.05 U g(-1) body weight of human FVIII intravenously within 24 h after birth and repeated injections as adults. In contrast, high FVIII antibody titers (>50 Bethesda Units mL(-1)) developed in seven of 13 mice injected on day 3 postpartum and in all adult mice not treated neonatally. One of nine mice and three of 17 mice developed high-titer antiFVIII inhibitory antibody when they were treated initially with 2-fold (0.1 U g(-1) body weight) and 10-fold higher doses (0.5 U g(-1) body weight) FVIII on day 0, respectively. A human FVIII-specific T-cell proliferative response was absent in splenocytes from neonatally treated mice. The tolerance was FVIII specific because antitoxoid antibodies developed after immunization with tetanus toxoid. Splenocytes failed to proliferate or produce interferon (IFN)-gamma in response to FVIII stimulation, yet still secreted interleukin-2. A proliferative response was restored with exogenous IFN-gamma or interleukin-12, suggesting that lack of inhibitor to FVIII was due to IFN-gamma-dependent anergy. Thus, exposure on day 0 to physiological levels of FVIII antigen might be important for induction of immune tolerance. This immune tolerance model may provide a basis for new approaches to prevention of FVIII inhibitors during replacement therapy.

Animals↗

PubMed2004

Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice.

BACKGROUND AND AIMS: Gastric intestinal metaplasia, which is mainly induced by Helicobacter pylori infection, is thought to be a precancerous lesion of gastric adenocarcinoma. Intestinal metaplastic mucosa expresses intestine specific homeobox genes, Cdx1 and Cdx2, in the human gastric mucosa. We and others have reported that ectopic expression of Cdx2 in the gastric epithelium generates intestinal metaplasia in the transgenic mouse model. METHODS: To clarify the differences in the roles of Cdx1 and Cdx2 in intestinal metaplasia, we generated transgenic mice expressing Cdx1 in the gastric mucosa and compared Cdx1 induced gastric mucosal morphological changes with Cdx2 induced intestinal metaplasia. RESULTS: The gastric mucosa in Cdx1 transgenic mice was completely replaced by intestinal metaplastic mucosa, consisting of all four intestinal epithelial cell types: absorptive enterocytes, goblet, enteroendocrine, and Paneth cells. Paneth cells, which were not recognised in Cdx2 transgenic mice, were in the upper portion of the intestinal metaplastic mucosa. Pseudopyloric gland metaplasia, which was induced in Cdx2 transgenic mice, was not recognised in Cdx1 transgenic mice. Proliferating cell nuclear antigen (PCNA) positive cells were diffusely scattered in Cdx1 induced intestinal metaplastic mucosa while PCNA positive cells in Cdx2 induced intestinal metaplastic mucosa were in the base of the metaplastic mucosa. Intestinal metaplastic mucosa of Cdx1 transgenic mouse stomach was significantly thicker than that of wild-type or Cdx2 transgenic mouse stomach. CONCLUSIONS: We have confirmed that Cdx1 induced gastric intestinal metaplasia but that it differed from Cdx2 induced intestinal metaplasia in differentiation, structure, and proliferation.

Animals↗

PubMed2003

Temporal profile of experimental ischemic edema after threshold amount of insult to induce infarction--ultrastructure, gravimetry and Evans' blue extravasation.

When a threshold amount of temporary ischemic insult to induce focal infarction was given to the unilateral cerebral hemisphere of gerbils, a small focal infarct surrounded by a wide penumbra developed in the rostral portion of the cerebral cortex. During the first 5 hours following recirculation, whole astrocytic cell bodies and processes in the ischemic hemisphere were swollen, with an increase in the number of glycogen granules and in number and size of mitochondria. This swelling was an active reaction of astrocytes for neuronal protection, scavenging potassium, glutamate, and other neuronal metabolic products, and for generating fuels for neurons (cyto-reactive edema). This reactive astrocytic swelling continued in the penumbra, but some dead neurons were found disseminated among the surviving neurons. Whereas, at 12 approximately 48 hours, focal infarction developed in which all cell membranes lost their Gibbs-Donnan's equilibrium due to energetic failure of their membranous Na+/K+ ATPase. This is the cytotoxic edema (cyto-necrotic edema). In the infarct focus, when pericapillary astrocytic end-feet were damaged, the capillary BBB was broken; and thus vasogenic edema was superimposed on the cytotoxic edema.

Animals↗

PubMed2001

Extensive neuronal localization and neurotrophic function of fibroblast growth factor 8 in the nervous system.

Fibroblast growth factor (FGF) 8 has been well established to play a critical role in the early development of the central nervous system (CNS). We report here extensive neuronal localization and neurotrophic function of FGF8 in the nervous system. In sections of mouse embryos at E10.5, FGF8 was immunohistochemically found in neurons at the marginal zones of the CNS and in the dorsal root ganglia (DRG). Neuronal localization of FGF8 was marked at later embryonic stages and in adults, involving most of the central and peripheral neurons, including intermuscular enteric neurons, DRGs, and paraaortic sympathetic ganglia. Functionally, FGF8 promoted neurite outgrowth in human neuroblastoma SK-N-MC cells as well as in rat pheochromocytoma PC12 cells, suggesting that FGF8 acts as a neurotrophic factor. FGF8 also supported neuronal survival and differentiation in cultured human neural progenitor cells. In a cell growth assay, treatment with 50 ng/ml FGF8 on human cultured neuroblastoma SK-N-MC and IMR32 cells attenuated the growth of both. In accordance with these in vitro findings, the immunohistochemical analysis on human neurological diseases showed that FGF8 expression is evident in differentiating histological types of neuroblastoma and ganglioneuroblastoma, and that the levels of FGF8 immunoreactivity in the substantia nigra from Parkinson's disease are significantly lower than those in age-matched controls. Taken together, the present findings strongly suggest that FGF8 acts as a more generalized neurotrophic factor than previously reported.

Animals↗

PubMed2001

Green fluorescent protein-transgenic rat: a tool for organ transplantation research.

The purpose of this study is to evaluate green fluorescent protein (GFP) transgenic rats for use as a tool for organ transplantation research. The GFP gene construct was designed to express ubiquitously. By flow cytometry, the cells obtained from the bone marrow, spleen, and peripheral blood of the GFP transgenic rats consisted of 77, 91, and 75% GFP-positive cells, respectively. To examine cell migration of GFP-positive cells after organ transplantation, pancreas graft with or without spleen transplantation, heart graft with or without lung transplantation, auxiliary liver and small bowel transplantation were also performed from GFP transgenic rat to LEW (RT1(1)) rats under a 2-week course of 0.64 mg/kg tacrolimus administration. GFP-positive donor cells were detected in the fully allogenic LEW rats after organ transplantation. These results showed that GFP transgenic rat is a useful tool for organ transplantation research such as cell migration study after organ transplantation without donor cell staining.

Animals↗

PubMed2001

Purification of activins from androgen-independent Shionogi carcinoma cells demonstrates enhanced expression of activin betaB-subunit under androgen-depleted cell conditions in vitro and in vivo.

Here, we report characterization of growth factors secreted from androgen-independent mouse mammary Shionogi carcinoma cells. Previous isolation of fibroblast growth factor 8 (FGF8) from androgen-dependent Shionogi carcinoma SC-3 cells prompted us to characterize growth factors secreted from the androgen-independent cells. After several purification procedures, mitogens for NIH3T3 cells from the androgen-independent cells were identified as activins on the grounds that activin betaA- and betaB-subunits are detected in the active fractions by Western blotting and that the growth-promoting effects by the active fractions are specifically inhibited in the presence of follistatin. In addition, exogenous activins, but not inhibin, stimulated the growth of NIH3T3 cells in a dose-dependent manner. Interestingly, transcripts of activin betaB-subunit were predominantly found in the androgen-independent cells while its betaA-subunit was universally expressed in both androgen-dependent and -independent Shionogi carcinoma cells. In concordant with this in vitro finding, transcripts of activin betaB-subunit were enhanced in murine prostates after castration. Therefore, expression of activin betaB-subunit, but not its betaA-subunit, is likely to be related with androgen-depleted cell conditions in prostates, and possibly in androgen-related cancers.

3T3 Cells↗

PubMed2001

Isolation of an androgen-inducible novel lipocalin gene, Arg1, from androgen-dependent mouse mammary Shionogi carcinoma cells.

Here we report isolation of an androgen-regulated novel gene from an androgen-dependent mouse mammary Shionogi carcinoma SC-3 cell line. Using a polymerase chain reaction-based subtraction method and Northern blotting analysis, we isolated four androgen-inducible genes from SC-3 cells. Nucleotide sequencings identified three of the genes as cyclin D1, beta-catenin, and fatty acid synthase, respectively, but the fourth, a gene tentatively named as Arg1 (androgen-regulated gene 1), remained undefined. The cloned 2.0-kb sized Arg1 cDNA encoded 414 amino acid sequences. The deduced amino acid sequences, sharing about 30% homology with cathepsin family members at a protein level, had relatively conserved residues around the three proteinase active sites reported earlier. In Northern blotting, Arg1 mRNA was found in kidney, heart, lung, and to a lesser degree, in spleen and liver. Its transcripts were also detected in male reproductive organs on RT-PCR. In addition, its expression levels in prostate were markedly reduced after castration. Unexpectedly, Arg1-expressing COS1 cells showed no significant proteinase activity to various synthesized substrates under neutral or acidic conditions in this study. This might have been due to the replacement of the cysteinyl active site for proteinase to serine residue in the Arg1 amino acid sequences. Given that Arg1 also contains a lipocaline signature known as a binding motif for small hydrophobic molecules at the center of its amino acid sequences, Arg1 is a lipocalin family gene regulated by androgens in prostate and Shionogi carcinoma cells.

Amino Acid Sequence↗

PubMed2001

Gene gun-mediated oral mucosal transfer of interleukin 12 cDNA coupled with an irradiated melanoma vaccine in a hamster model: successful treatment of oral melanoma and distant skin lesion.

Malignant melanoma involving the oral cavity has a highly metastatic potential. Curative surgery is required to resect extensive oral tissues and often results in dysfunction as well as a severe cosmetic deformity in patients with the disease. An alternative technology for the local and sustained delivery of cytokines for cancer immunotherapy has been shown to induce tumor regression, suppression of metastasis, and development of systemic antitumor immunity. However, local immunization of the oral cavity has not previously been studied. In this study, we examined the efficacy of particle-mediated oral gene transfer on luciferase and green fluorescent protein production. The results showed that these proteins were more significantly expressed in oral mucosa than the skin, stomach, liver, and muscle. Using an established oral melanoma model in hamsters, particle-mediated oral gene gun therapy with interleukin (IL) 12 cDNA was then conducted. The results indicated that direct bombardment of mouse IL-12 cDNA suppressed tumor formation and improved the survival rate. The skin tumor model created by inoculation of melanoma cells was also significantly inhibited by the oral bombardment of IL-12 cDNA coupled with an irradiated melanoma vaccine administrated to the oral mucosa, compared to treatment with a percutaneous vaccine. IL-12 gene gun therapy, combined with an oral mucosal vaccine, induced interferon-gamma mRNA expression in the host spleen for a long time. These results suggest that immunization of oral mucosa may induce systemic antitumor immunity more efficiently than immunization of the skin and that oral mucosa may be one of the most suitable tissues for cancer gene therapy by means of particle-mediated gene transfer.

Animals↗

PubMed2001

Fluoroquinolone concentrations in plasma, urine, and bile after oral administration in rats with renal failure: useful technique for long-term bile collection.

Using a previously reported technique for bile collection, we studied the pharmacokinetics of levofloxacin (LVFX) and grepafloxacin (GPFX) in normal rats and in animals with renal failure. Continuous bile drainage was performed using normal and renal-failure Wistar rats. Oral GPFX or LVFX (40 mg/Kg) was administered. The drug concentrations in plasma, urine, and bile were determined by high-performance liquid chromatography. The area under the blood concentration-time curve (AUC) in each renal-failure rat was calculated. There were no significant differences in GPFX concentrations in the serum, urine, and bile between the renal-failure and normal rats, but the LVFX level in the urine of the renal-failure group was statistically significantly lower than in the normal group. The AUC of GPFX had an opposite correlation with the degree of renal failure, but that of LVFX was correlated.

Administration, Oral↗

PubMed2000

Proteoliposomes colocalized with endogenous mitochondria in mouse fertilized egg.

Colocalization of mitochondria is the first step of intermitochondrial interaction or fusion in a cell. Here, we showed colocalization between exogenous mitochondria and endogenous ones or between exogenous proteoliposomes and endogenous mitochondria in mouse fertilized eggs by confocal laser microscopy. Isolated mitochondria from mouse liver and proteoliposomes containing mitochondrial membrane were directly labeled with red fluorescent aliphatic marker, PKH26, which is incorporated into lipid membrane, and then were microinjected into fertilized mouse eggs. Exogenous mitochondria appeared to be almost colocalized with endogenous mitochondria at the 4- and 8-cell stages, when mitochondria were stained with Rhodamine 123 (green fluorescent marker). On the contrary, when liposomes consisted of soy bean phospholipid were microinjected into the eggs as a control, their localization was different from that of endogenous mitochondria. Next, the submitochondrial particles and proteoliposomes were microinjected. Both the proteoliposomes and the submitochondrial particles appeared to colocalize with endogenous mitochondria at the 4-cell stage. These results suggest the existence of a factor that makes liposomes colocalize with mitochondria. Such a proteoliposome would be useful for the development of mitochondrial gene transfer techniques.

Animals↗

PubMed2000

Differential regulation of exonic regulatory elements for muscle-specific alternative splicing during myogenesis and cardiogenesis.

Muscle-specific isoform of the mitochondrial ATP synthase gamma subunit (F(1)gamma) was generated by alternative splicing, and exon 9 of the gene was found to be lacking particularly in skeletal muscle and heart tissue. Recently, we reported that alternative splicing of exon 9 was induced by low serum or acidic media in mouse myoblasts, and that this splicing required de novo protein synthesis of a negative regulatory factor (Ichida, M., Endo, H., Ikeda, U., Matsuda, C., Ueno, E., Shimada, K., and Kagawa, Y. (1998) J. Biol. Chem. 273, 8492-8501; Hayakawa, M., Endo, H., Hamamoto, T., and Kagawa, Y. (1998) Biochem. Biophys. Res. Commun. 251, 603-608). In the present report, we identified a cis-acting element on the muscle-specific alternatively spliced exon of F(1)gamma gene by an in vivo splicing system using cultured cells and transgenic mice. We constructed a F(1)gamma wild-type minigene, containing the full-length gene from exon 8 to exon 10, and two mutants; one mutant involved a pyrimidine-rich substitution on exon 9, whereas the other was a purine-rich substitution, abbreviated as F(1)gamma Pu-del and F(1)gamma Pu-rich mutants, respectively. Based on an in vivo splicing assay using low serum- or acid-stimulated splicing induction system in mouse myoblasts, Pu-del mutation inhibited exon inclusion, indicating that a Pu-del mutation would disrupt an exonic splicing enhancer. On the other hand, the Pu-rich mutation blocked muscle-specific exon exclusion following both inductions. Next, we produced transgenic mice bearing both mutant minigenes and analyzed their splicing patterns in tissues. Based on an analysis of F(1)gamma Pu-del minigene transgenic mice, the purine nucleotide of this element was shown to be necessary for exon inclusion in non-muscle tissue. In contrast, analysis of F(1)gamma Pu-rich minigene mice revealed that the F(1)gamma Pu-rich mutant exon had been excluded from heart and skeletal muscle of these transgenic mice, despite the fact mutation of the exon inhibited muscle-specific exon exclusion in myotubes of early embryonic stage. These results suggested that the splicing regulatory mechanism underlying F(1)gamma pre-mRNA differed between myotubes and myofibers during myogenesis and cardiogenesis.

ATP Synthetase Complexes↗

PubMed2000

3-Nitropropionic acid preconditioning ameliorates delayed neurological deterioration and infarction after transient focal cerebral ischemia in gerbils.

The effect of 3-nitropropionic acid (3-NP), a selective inhibitor of succinic dehydrogenase, preconditioning on postischemic neurological deterioration and infarction was examined in gerbils after transient ischemia. The animals were pretreated with 1-80mg/kg of 3-NP 1 day before ischemia induced by two 10-min occlusions of the left common carotid artery. Four milligrams per kilogram 3-NP pretreatment significantly ameliorated postischemic neurological deterioration (stroke index at 7 days postischemia, 1.4+/-1.5 vs. 7.4+/-5.4 in 4 mg/kg-pretreated vs. non-pretreated animals: mean+/-SD) and reduced infarct volume (24+/-4.8 vs. 43+/-12 mm(3)). One and 20 mg/kg 3-NP induced milder neuroprotection, and 80 mg/kg 3-NP aggravated postischemic stroke symptoms and infarction. Thus, appropriate doze of 3-NP preconditioning is effective in ameliorating the postischemic neurological deterioration and reducing infarct volume.

Animals↗

PubMed2000

Combined therapy utilizing a novel Na+/H+ exchange inhibitor (SM-20220) and THAM for ischemic brain edema.

We investigated in the gerbil model whether the therapeutic effect of a novel Na+/H+ exchange inhibitor SM-20220 on ischemic brain edema could be enhanced by improving the decreased intracellular pH with an alkalizing agent, tris (hydroxymethyl) aminomethane (THAM). The left carotid artery of the animals was occluded twice for 10 min at a 5 hr interval. Ischemia-positive animals were selected and classified into the SM-20220- (0.5 mg/kg, i.p.) THAM- (2.0 ml/kg, i.v., 0.3M-THAM), combination of SM-20220 (0.5 mg/kg, i.p.) and THAM (2.0 ml/kg, i.v.), and vehicle- (0.9% saline, i.p.) treatment groups. Each agent was administered at 0, 6, 12 and 36 hr after recirculation following the 2nd episode of ischemia. The brain water, sodium and potassium contents were measured at 12, 24, and 48 hr after recirculation. The water content of the ischemic hemisphere 12 hr after recirculation was significantly lower in the combination-treated group (79.02%; P < 0.05) than in either the SM-20220- (79.28%) or THAM-treated group (79.32%). At 24 hr after recirculation the water content was significantly lower in the combination-treated group (79.83%, P < 0.05) than in the vehicle group (80.95%). At 48 hr after recirculation there were no significant differences in the water content between the vehicle group and any of the other treatment groups. The changes in brain water (delta H2O) and sodium plus potassium (delta Na + delta K) content in the ischemic hemisphere showed a significant correlation in each group. The combined treatment with the novel Na+/H+ exchange inhibitor SM-20220 and THAM is more effective on ischemic brain edema than treatment with a single agent. The results of this study indicate that improvement of intra- and extracellular acidosis by THAM infusion enhanced the activity of the NHE inhibitor SM-20220.

Amides↗

PubMed2000

Evolution of energy failure after repeated cerebral ischemia in gerbils.

We have examined the regional differences in the evolution of energy failure in experimental focal cerebral ischemia. In gerbil brain subjected to repeated unilateral common carotid artery occlusion, the tissue ATP content, pH and succinic dehydrogenase activity decreased at different rates after the circulation had been restored in various cerebral regions. Light microscopical infarction became apparent at different rates following the impairment of the energy metabolism in these regions. In brain cortex with selective neuronal necrosis, only minor alterations in energy metabolism were detectable over a 7-day period following the restoration of the circulation. The present data show that the rate of energy failure is significantly different in various cerebral regions after repeated periods of cerebral ischemia in the gerbil. A slowly evolving impairment of the cerebral energy metabolism after circulation of the brain has been restored appears to be indispensable for the delayed formation of infarction after transient cerebral ischemia.

Acid-Base Equilibrium↗

PubMed2000

Regional differences in the rate of energy impairment after threshold level ischemia for induction of cerebral infarction in gerbils.

The development of infarction and/or selective neuronal death in the brain after transient cerebral ischemia depends on the severity of the ischemic episode. After transient cerebral ischemia of the threshold level for the induction of infarction, both changes evolve slowly in various postischemic regions. We examined the relationship of disturbances of energy metabolism to infarction and selective neuronal death in various regions of the postischemic brain subjected to two 10-min occlusions of the unilateral common carotid artery. Our results indicated that in various cerebral regions that developed infarction, the tissue ATP content, in parallel with the succinic dehydrogenase activity, fell to their lowest levels at different times over a 4-day period after circulation had been restored (earliest to latest: dorsolateral thalamus > dorsolateral caudate > chiasmal level cortex > hippocampal CA3 sector > hippocampal CA sector). In the cortex at the infundibular level, disseminated selective neuronal death developed over a 7-day period following restoration of circulation; it was accompanied by only a slight alteration in energy metabolism. The present results indicate that regional differences existed in the rate of energy impairment and evolving infarction in the postischemic gerbil brain. Energy impairment, in association with mitochondrial enzymatic dysfunction, seems to be indispensable for the delayed manifestation of cerebral infarction but not for disseminated selective neuronal death.

Adenosine Triphosphate↗