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Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production on the reported behavioral deficits of EGF-injected mice. These results support the argument that aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Although chronic cardiac dysfunction is known to progressively exacerbate renal injury, a condition known as type 2 cardiorenal syndrome (CRS), the mechanism responsible is largely unknown. The present study was undertaken to clarify the mechanism of renal injury in rats with both unilateral nephrectomy (NX) and surgically induced myocardial infarction (MI), corresponding to a model of type 2 CRS. Compared with a control group, rats with both MI and NX (MI+NX) exhibited progressive proteinuria during the experimental period (34 wk after MI surgery), whereas proteinuria was not observed in rats with MI alone and was moderate in rats with NX alone. The proteinuria in rats with MI+NX was associated with renal lesions such as glomerulosclerosis and infiltration of mononuclear cells and upregulation of the renal proinflammatory and -fibrotic cytokine and angiotensin II type 1a receptor (AT1aR) genes. In contrast, plasma renin activity was lowered in rats with MI+NX. Immunohistochemistry revealed that the increased AT1R protein was present mainly in renal interstitial mononuclear cells. Olmesartan medoxomil, an AT1R blocker, markedly reduced the proteinuria and infiltration of mononuclear cells, whereas spironolactone, a mineralocorticoid receptor blocker, did not. The present findings demonstrate the pathogenetic role of renal interstitial AT1R signaling in a model of type 2 CRS, providing evidence that AT1R blockade can be a useful therapeutic option for this syndrome.

Abnormal signaling mediated by epidermal growth factor (EGF) or its receptor (ErbB) is implicated in the neuropathology of schizophrenia. Previously, we found that the anthraquinone derivative emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits ErbB1 signaling and ameliorates behavioral deficits of the schizophrenia animal model established by EGF challenge. In the present study, we assessed acute and subchronic effects of its administration on methamphetamine-triggered behavioral hyperactivation in rats. Prior subchronic administration of emodin (50mg/kg/day, 5days, p.o.) suppressed both higher acoustic startle responses and hyperlocomotion induced by acute methamphetamine challenge. In parallel, emodin also attenuated methamphetamine-induced increases in dopamine and its metabolites and decreases in serotonin and its metabolites. Emodin administered alone also had an effect on stereotypic movement but no influence on horizontal or vertical locomotor activity. In contrast to pre-treatment, post-treatment with emodin had no effect on behavioral sensitization to methamphetamine. Administration of emodin in parallel to or following repeated methamphetamine challenge failed to affect hyperlocomotion induced by methamphetamine re-challenges. These findings suggest that emodin has unique pharmacological activity, which interferes with acute methamphetamine signaling and behavior., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fibrosis is the final common pathway for various tissue lesions that lead to chronic progressive organ failure, and consequently effective antifibrotic drugs are strongly desired. However, there are few animal models in which it is possible to evaluate fibrosis sensitively in a short period of time. We therefore generated two transgenic rats harboring a firefly luciferase reporter gene under the control of the 5'-flanking region of rat α(1)(I) collagen (Col1a1-Luc Tg rats) and α(2)(I) collagen (Col1a2-Luc Tg rats). The luciferase activities of these transgenic rats were highly correlated with the hydroxyproline content in various organs. In unilateral ureteral obstruction (UUO), a well-characterized model of renal fibrosis, the luciferase activity in obstructed kidneys showed a significant increase after even 3 days of UUO, while the hydroxyproline content showed little increase. In addition, the renal hydroxyproline content had a higher correlation with the luciferase activity than α(1)(I) collagen mRNA level for over 2 wk after UUO. Although both an ANG II type 1 receptor blocker (ARB), olmesartan, and a transforming growth factor-β (TGF-β) type I receptor kinase (ALK5) inhibitor, SB-431542, inhibited renal luciferase activities in UUO, only SB-431542 inhibited luciferase activity induced by TGF-β1 in isolated glomeruli. Double immunostaining for luciferase and α-smooth muscle actin (α-SMA) revealed that some α-SMA-positive tubular epithelial cells and tubular interstitial cells produced type I collagen, which would lead to renal fibrosis. Thus collagen reporter transgenic rats would be very useful for the evaluation of antifibrotic effects and analysis of their mechanisms.

Novel protein synthesis is an essential element of various learning paradigms. Although pharmacological and genetic strategies have indicated the importance of translational activation in learning, the specific signaling pathways that are activated in the brain remain unclear. Here, we show that mammalian target of rapamycin (mTOR), a key serine/threonine protein kinase in translational control, is activated in hippocampus of the learning rat as revealed by in vitro kinase assay, Western blotting and immunohistochemistry. The substrates of mTOR, eukaryotic initiation factor 4E-binding protein (4EBP) and p70S6 kinase (p70S6K) are phosphorylated, and total protein synthesis is enhanced, in the learning hippocampus. Furthermore, the inhibition of mTOR by chronic infusion of rapamycin, a specific inhibitor of mTOR, into the ventricle retards the establishment of spatial learning. Thus, mTOR signaling is activated during learning, enhances translation, and plays a crucial role in the spatial learning., (2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction.

Olmesartan medoxomil is a new angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is converted to the active metabolite olmesartan. Olmesartan does not undergo further metabolism and does not interact with cytochrome P450 enzymes. Olmesartan is a potent ARB with high selectivity for the type 1 (AT(1)) receptor subtype and shows insurmountable antagonism against the AT(1) receptor in vascular tissues. This antagonistic mode, which could be attributed to tight binding of this drug to the receptor, would underlie the potent and persistent action of olmesartan medoxomil in vivo. In fact, oral administration of olmesartan medoxomil produces a potent and long-lasting antihypertensive action without inducing tachycardia. The preventive effects of olmesartan medoxomil on end-organ damage in the kidney, heart, and blood vessels have been demonstrated in various animal models. In clinical studies, olmesartan medoxomil is shown to be well tolerated and have an excellent safety profile that is comparable to that of placebo. Head-to-head comparisons with other ARBs (losartan, valsartan, irbesartan, and candesartan cilexetil) conducted in the United States and Europe have revealed that olmesartan medoxomil is superior to these other ARBs in lowering blood pressure. These facts suggest that olmesartan medoxomil would be beneficial for the treatment of hypertension and other end-organ diseases.

Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensive/NIH-corpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk. BP, renal function, glucose and insulin levels, and proteinuria were monitored. Glomerular lesions and kidney pentosidine content were assessed at the end of the study. Olmesartan (1 and 5 mg) significantly reduced BP and kidney pentosidine content and improved histologic renal damage and proteinuria. The changes were dose-dependent. The effect of hydralazine (5 mg) was similar to that of olmesartan (1 mg) but reached statistical significance only for kidney pentosidine content. The similarity of both drugs' effects on kidney damage and proteinuria suggest that renoprotection does not hinge on manipulation of RAS in these rats. By contrast, the inhibition of renal pentosidine formation assessed both by immunohistochemistry and HPLC suggests a critical role of advanced glycation end product (AGE) formation together with hypertension in the genesis of diabetic nephropathy. This view is supported by the correlation found between renal pentosidine content and proteinuria. The unsuspected AGE-lowering effect of hydralazine was further confirmed in vitro and elucidated; it is due to both reactive carbonyl compounds trapping and modifications of the oxidative metabolism. It is concluded that AGE inhibition should be included in the therapeutic strategy of DN.

Abnormal development of the brain is implicated in the etiology and/or pathology of various psychiatric diseases, including schizophrenia. Current evidence indicates that neurotrophic factors can strongly influence neuronal phenotypic differentiation and subsequent neuronal function in synaptic plasticity. Among various neurotrophic factors, the expression of brain-derived neurotrophic factor(BDNF) and epidermal growth factor (EGF) is impaired in the brain as well as in the periphery of patients with schizophrenia. Based on this result, a novel animal model for schizophrenia has been established by perturbing the neurotrophic signaling during development. This review summarizes the latest progress of these studies.

Regulation of gene transcription via the cyclic adenosine 3',5'-monophosphate (cAMP)-mediated second messenger pathway has been implicated in learning and memory. Although the cAMP response element-binding protein (CREB) is an important transcription factor involved in long-term memory, it remains to be determined whether the CREB-dependent events are attributed to spatial learning and memory in a radial arm maze. Here we demonstrate that cAMP-dependent protein kinase A (PKA) and CREB are activated in the course of spatial learning. The radial maze training in rats resulted in a significant increase in PKA and CREB phosphorylation in the hippocampus in the course of spatial learning, which was followed by spatial memory formation. On the other hand, neither the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) nor the mRNA level of brain-derived neurotrophic factor was significantly affected. These results suggest that activation of the PKA/CREB signaling pathway in the hippocampus plays an important role in spatial memory formation.

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.