Biomedical subjects

Hae Sook Noh

Publications and source records attributed to Hae Sook Noh.

15 recordsLinked to original sources

PubMed2006

Action of citicoline on rat retinal expression of extracellular-signal-regulated kinase (ERK1/2).

Citicoline is an essential endogenous intermediate in the biosynthesis of phosphatidylcholine, which acts as a therapeutic agent in models of central nervous system injury and neurodegenerative diseases. The present study investigated the effects of citicoline on extracellular-signal-regulated kinase 1/2 (ERK1/2) expression in the rat retina after kainic acid (KA) treatment. KA (6 nmol) was injected into the vitreous of the rat eyes. The animals were then injected intraperitoneally with citicoline (500 mg/kg) twice daily after the KA injection. The neuroprotective effects of citicoline were estimated by evaluating temporal changes in ERK1/2 using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL), immunoblotting and immunohistochemical techniques. The expression of phosphorylated ERK1/2 was slightly decreased after 6 h, and significantly reduced after 12 h, in the rats receiving the KA injection plus citicoline treatment. Our results demonstrated that citicoline decreased the activation of ERK1/2 due to the KA treatment, suggesting that it exerts its neuroprotective activity by reducing the concentrations of proteins involved in apoptosis.

Animals↗

PubMed2006

Increased nitric oxide caused by the ketogenic diet reduces the onset time of kainic acid-induced seizures in ICR mice.

Although the antiepileptic effects of the ketogenic diet (KD) are well documented, the mechanisms underlying this action remain obscure. Nitric oxide (NO) has long been thought to play a role in regulating seizures. However, the effects of the KD on endogenous NO production have not been characterized. Therefore, the present study was designed to examine the effect of the KD on endogenous NO production, as well as the precise role of NO in kainic acid (KA)-induced seizures, in male ICR mice. We first found that preadministration of the KD for 4 weeks increased endogenous NO generation in the hippocampus. We also demonstrated that the increase in NO induced by the KD resulted from increased neuronal NO synthase (nNOS) activity and exerted an antiepileptic effect on KA-induced seizures, based on the results of experiments using NOS-knockout mice and two NOS inhibitors, N-omega-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI). These data suggest that the antiepileptic effects of the KD might be mediated, at least in part, by increased NO levels in the hippocampus.

3-Hydroxybutyric Acid↗

PubMed2006

Acetoacetate protects neuronal cells from oxidative glutamate toxicity.

Glutamate cytotoxicity contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as epilepsy and ischemia. We previously reported that a high-fat and low-carbohydrate diet, the ketogenic diet (KD), protects against kainic acid-induced hippocampal cell death in mice. We hypothesized based on these findings that ketosis resulting from KD might inhibit glutamate cytotoxicity, resulting in inhibition of hippocampal neuronal cell death. Therefore, we investigated the role of ketone bodies [acetoacetate (AA) and beta-hydroxybutyrate (beta-OHB)] both in a mouse hippocampal cell line (HT22) and in rat primary hippocampal neurons. As a result, we found that pretreatment with 5 mM lithium AA and 4 mM Na beta-OHB protected the HT22 hippocampal cell line and primary hippocampal neuronal culture against 5 mM glutamate toxicity and that up to 2 hr of pretreatment with 5 mM AA had a protective effect against 5 mM glutamate toxicity in the HT22 cell line. Pretreatment with 5 mM AA decreased ROS production of HT22 cell line at 2 and 8 hr exposure of glutamate, and it decreased the appearance of annexin V-positive HT22 cells, which are indicative of an early stage of apoptosis, and propidium iodide-positive HT22 cells, which are indicative of necrosis.

Acetoacetates↗

PubMed2006

Ketogenic diet protects the hippocampus from kainic acid toxicity by inhibiting the dissociation of bad from 14-3-3.

The ketogenic diet (KD) is often effective for intractable epilepsy, but its antiepileptic mechanisms remain largely unknown. Within the cell death/survival pathway, Akt and its downstream protein Bad play an important role in kainic acid (KA)-induced cell death. Therefore, we investigated the effects of a KD on KA-induced changes in the Akt/Bad/14-3-3 signaling pathway by evaluating Akt, Bad, 14-3-3, and cleaved caspase-3 expression levels as well as their relative interactions. Our results showed that a KD did not affect the expression levels of Akt, Bad, Bcl-xL, Bax, and 14-3-3 but increased phospho-Akt [serine 473; p-Akt (Ser473)] and phospho-Bad [serine 136; p-Bad (Ser136)] expression levels as well as decreased cleaved caspase-3 levels following a KA-induced seizure in the hippocampus. Furthermore, we found that a KD increased the protein-protein interaction between 14-3-3 and p-Bad (Ser136), which might be phosphorylated by p-Akt (Ser473), and decreased interaction of Bad and Bcl-xL. These results suggest that a KD might protect, at least partially, the hippocampus from KA-induced cell death via inhibiting the dissociation of Bad from 14-3-3.

14-3-3 Proteins↗

PubMed2005

Ketogenic diet decreases the level of proenkephalin mRNA induced by kainic acid in the mouse hippocampus.

The ketogenic diet (KD) has been used to control medically refractory epilepsy in children for more than 80 years. Despite the clinical efficacy of the KD, its underlying bases are still obscure. Previous work from our laboratory has established that the KD has an antiepileptic and neuroprotective effect in the kainic acid (KA)-induced seizure model. The neuronal excitation caused by KA leads to increases in the expression of a variety of genes, including immediate-early genes and opioid peptides derived from proenkephalin (PENK) and prodynorphin (PDYN). In particular, the up-regulated PENK gene that is induced by KA in the hippocampal dentate granule cells has proconvulsant properties. PENK is regulated by the c-jun amino-terminal kinase (JNK) signaling pathway, the crucial role of which is involved in the regulation of transcription factors, such as Jun and Fos. In the present study, we examined the effect of the KD on the increase of PENK, Fos, Jun, AP-1 DNA-binding activity and JNK gene expression induced by KA in the mouse hippocampus. Using in situ hybridization and northern blot analysis, we found that the KD significantly decreases the level of PENK gene expression induced by KA of the granular cells in the hippocampus. In addition, we have also found that KD diminished KA-induced AP-1 DNA-binding activity, Fos and Jun expression, and phoshorylated form of the three types of JNKs. These results suggest that the KD suppresses KA-induced activation of JNK signaling pathways, followed by a decrease of PENK gene expression in the hippocampus, thereby resulting in antiepileptic effects.

Animals↗

PubMed2005

Estradiol prevents the injury-induced decrease of Akt activation and Bad phosphorylation.

Estradiol prevents neuronal cell death through the inhibition of apoptotic signals and the activation of cell survival signals. This study investigated whether estradiol modulates the anti-apoptotic signal through the activation of Akt and its downstream targets, including Bad, Bcl-x(L), and 14-3-3. Adult female rats were ovariectomied and treated with estradiol prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 h after MCAO and infarct volumes were analyzed. We confirmed that estradiol significantly reduces infarct volume and decreases the positive cells of TUNEL staining in the cerebral cortex. Potential activation was measured by phosphorylation of Akt at Ser473 and Bad at Ser136 using Western blot analysis. Estradiol prevents the injury-induced decrease of pAkt, pBad, and Bcl-x(L). Further, in the presence of estradiol, the interaction of pBad and 14-3-3 increased, compared to that of oil-treated animals. Our findings suggest that estradiol prevents cell death due to brain injury and that Akt activation and Bad phosphorylation by estradiol mediated these protective effects.

14-3-3 Proteins↗

PubMed2005

Ketogenic diet prevents clusterin accumulation induced by kainic acid in the hippocampus of male ICR mice.

We investigated the effect of ketogenic diet (KD) on clusterin accumulation in the kainic acid (KA)-induced seizure model. Two days after KA administration, strong clusterin-like immunoreactivity (IR) was detected in the hippocampus in the normal diet (ND)-fed mice. But in the KD-fed mice, few clusterin-like IR was detected. These results indicate that KD has neuroprotective effects throughout diminishing nuclear clusterin accumulation that is involved in caspase-3 independent cell death mechanism.

Animal Nutritional Physiological Phenomena↗

PubMed2005

Ketogenic diet increases calbindin-D28k in the hippocampi of male ICR mice with kainic acid seizures.

The ketogenic diet (KD) increased the expression of calbindin-D(28k) (CB) in the interneurons of the hippocampus compared with the normal diet (ND)-fed mice. Also, 2 days after kainic acid (KA) administration, numerous CB-expressing astrocytes were found in the KD-fed mice compared with those of the ND-fed mice. These results suggest that the neuroprotective effect of the KD on the KA-induced toxicity may be, in part, mediated via an increased expression of CB.

Animals↗

PubMed2005

Changes in rhodopsin kinase and transducin in the rat retina in early-stage diabetes.

To establish changes in phototransduction in diabetes, the effects of high glucose on rhodopsin kinase (RK) and transducin (G(t)), as well as recoverin, were examined in the retina of STZ-induced diabetic rats. Diabetes was induced by single intraperitoneal injection of STZ (50mg/kg) to Sprague-Dawley (SD) rats and the animals were sacrificed after 6 weeks. Immunohistochemistry (IHC) and Western blot analysis were carried out using antibodies against RK and G(talpha) (alpha subunit of G(t)) in the STZ-induced diabetic retina and the control retina. The expression level of recoverin protein was also analysed. In the diabetic retina, while the expression of RK protein increased, that of G(talpha) and recoverin proteins decreased. RK immunoreactivity (IR) appeared generally in the retina, and its signal increased in the outer limiting membrane (OLM), some rod cells in the outer segment layer (OSL) and at the tip of the outer plexiform layer (OPL) in the diabetic retina. G(talpha)-IR also appeared in the OPL and in photoreceptor layer. In the diabetic retina, G(talpha)-IR significantly decreased in the OPL, indicating RK-IR increase. This study illustrates the alterations in RK, G(talpha) and recoverin in the diabetic retina that may induce dysfunctions in phototransduction even in early-stage diabetes.

Animals↗

PubMed2005

Neuroprotective effect of citicoline against KA-induced neurotoxicity in the rat retina.

We examined whether citicoline has neuroprotective effect on kainic acid (KA)-induced retinal damage. KA (6 nmol) was injected into the vitreous of rat eyes. Rats were injected intraperitoneally with citicoline (500 mgkg-1, i.p.) twice (09:00 and 21:00) daily for 1, 3 and 7 days after KA-injection. The neuroprotective effects of citicoline were estimated by measuring the thickness of the various retinal layers. In addition, immunohistochemistry was conducted to elucidate the expression of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH). Morphometric analysis of retinal damage in KA-injected eyes showed a significant cell loss in the inner nuclear layer (INL) and inner plexiform layer (IPL) of the retinas at the 1, 3 and 7 days after KA injection, but not in the outer nuclear layers (ONL). At 1 and 3 days after citicoline treatment, no significant changes were detected in the retinal thickness and immunoreactivities of ChAT and TH. The immunoreactivities of ChAT and TH had almost disappeared in the retina after 7 days of KA injection. However, prolonged citicoline treatment for 7 days significantly attenuated the reduction of retinal thickness and immunoreactivities of ChAT and TH. The present study suggests that treatment with citicoline has neuroprotective effect on the retinal damage due to KA-induced neurotoxicity.

Animals↗

PubMed2004

A cDNA microarray analysis of gene expression profiles in rat hippocampus following a ketogenic diet.

The ketogenic diet (KD) is an effective therapy for medically intractable epilepsy, but its anticonvulsant mechanisms are unknown. Few studies to date have addressed the molecular changes following treatment with a KD. In the present study, we fed juvenile rats either a standard diet or a KD for 1 month, and then determined changes in hippocampal gene expression using cDNA microarray analysis (Clontech). To validate the microarray expression results, we also performed Northern blot and RT-PCR analysis on a small subset of affected genes. Among a total of 1176 cDNAs, 42 genes were strongly up- or down-regulated (>2-fold change over controls) by a KD. We found that the expression of mitochondrial ATP synthase beta subunit, mitochondrial ATP synthase D subunit (ATP5H) and mitochondrial ATP synthase beta subunit precursor (ATP5F) were especially increased in KD-treated group, whereas the KD down-regulated protein kinase C (PKC) beta and epsilon isoforms. Thus, the most prominent changes were seen in genes encoding proteins involved in mitochondrial metabolic and intracellular signal transduction pathways. Our data provide some insights into the complex cascade of cellular changes in the hippocampus induced by a KD, some of which may contribute to its anticonvulsant effects.

3-Hydroxybutyric Acid↗

PubMed2003

Suppression by ethanol of male reproductive activity.

Ethanol has been known to suppress reproductive activity in laboratory animals and humans through the inhibition of luteinizing hormone (LH) release by reduction of gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. There are, however, little data is available regarding the effect of ethanol on GnRH gene expression. Thus, the present study was designed to evaluate the effect of ethanol on GnRH gene expression and reproductive activity at all levels of the hypothalamus-pituitary-gonad (HPG) axis simultaneously. To this end, ethanol (3 g/kg i.p., 15% v/v in saline) was administered to adult male rats for 10 days. Serum levels of LH and testosterone were significantly decreased by ethanol. Using Northern blot analysis and in situ hybridization, the present study showed the reduction in GnRH mRNA levels in the hypothalamus by prolonged ethanol administration. The content of LH in the anterior pituitary was also significantly reduced by ethanol. In addition, steroidogenic acute regulatory protein (StAR) mRNA levels were significantly decreased by ethanol, suggesting a cause for the reduced production of testosterone under this condition. These results indicate that ethanol affects the HPG axis at all the levels. Especially, suppressed GnRH mRNA levels in the hypothalamus of ethanol-treated rats strongly demonstrated that hypothalamus is the major action site of ethanol on the HPG axis. Decreased serum LH level may affect the steroidogenesis in the testis, at least in part, through the inhibition of StAR gene expression that induces part of dysfunctions of reproductive activity.

Animals↗

PubMed2003

Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia.

Wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of a medicinal herb Scutellaria baicalensis Georgi, has been previously shown to have anti-inflammatory activities in various cell types including macrophages. In this work, we have found that wogonin is a potent neuroprotector from natural source. Wogonin inhibited inflammatory activation of cultured brain microglia by diminishing lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta, and nitric oxide (NO) production. Wogonin inhibited NO production by suppressing inducible NO synthase (iNOS) induction and NF-kappaB activation in microglia. Inhibition of inflammatory activation of microglia by wogonin led to the reduction in microglial cytotoxicity toward cocultured PC12 cells, supporting a neuroprotective role for wogonin in vitro. The neuroprotective effect of wogonin was further demonstrated in vivo using two experimental brain injury models; transient global ischemia by four-vessel occlusion and excitotoxic injury by systemic kainate injection. In both animal models, wogonin conferred neuroprotection by attenuating the death of hippocampal neurons, and the neuroprotective effect was associated with inhibition of the inflammatory activation of microglia. Hippocampal induction of inflammatory mediators such as iNOS and TNF-alpha was reduced by wogonin in the global ischemia model, and microglial activation was markedly down-regulated by wogonin in the kainate injection model as judged by microglia-specific isolectin B4 staining. Taken together, our results indicate that wogonin exerts its neuroprotective effect by inhibiting microglial activation, which is a critical component of pathogenic inflammatory responses in neurodegenerative diseases. The current study emphasizes the importance of medicinal herbs and their constituents as an invaluable source for the development of novel neuroprotective drugs.

Animals↗

PubMed2003

Cellular localization of pituitary adenylate cyclase-activating polypeptide in the rat testis.

Several growth factors are critical regulators of testicular development. Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to promote the differentiation and proliferation of various cell types and to stimulate the release of vascular endothelial growth factor during tissue growth. The present study aimed to evaluate the possible expression of PACAP in immature and adult rat testes by Northern blot analysis, in situ hybridization, and immunohistochemistry. PACAP transcripts were detected in both immature and adult tissues, but the level of PACAP expression depended on the age of the animal. It was expressed in the peritubular and interstitial cells of the 14-day-old testis and in seminiferous tubules of the 90-day-old-testis. It was strongly expressed in blood vessels at 14 days, moderately at 28 days and only weakly at 90 days. These results suggest that PACAP contributes to the growth and differentiation of peritubular and interstitial cells, and of blood vessels, during testicular development.

Animals↗

PubMed2003

The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice.

This study was designed to evaluate the antiapoptotic effects of a ketogenic diet (KD) through histological (cresyl violet staining, TUNEL staining and immunohistochemistry) and behavioral studies using kainic acid (KA, 25mg/kg i.p.)-induced seizures in male ICR mice. KA-induced seizure in rodents is widely used as an experimental model for human temporal lobe epilepsy because of their behavioral and pathological similarities. A KA-induced seizure causes neuronal damage in hippocampal pyramidal neurons and involves a caspase-3-mediated apoptotic pathway. In this study, the seizure onset time of the KD-fed group was delayed compared to that of the group fed a normal diet (ND) after a systemic KA injection. Histological studies revealed that KA caused pyknosis in most of the hippocampal areas in the ND-fed group, however, well-preserved pyramidal neurons were detected in the hippocampus of mice that had been on KD for 1 month, which began on postnatal day 21. The number of TUNEL-positive cells and caspase-3-positive cells in the hippocampus of the KD-fed group was lower than that of the ND-fed group. These findings indicate that KD has an antiepileptic effect via a neuroprotective action that involves the inhibition of caspase-3-mediated apoptosis of hippocampal neurons.

Animals↗