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Makoto Higuchi

Publications and source records attributed to Makoto Higuchi.

At least 19 recordsLinked to original sources
PubMed2007

In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems.

Neurotransmission mediated by substance P (SP) and NK(1) receptor has been implicated in the pathophysiology of analgesia, emesis and diverse neuropsychiatric conditions including depression and anxiety disorder. Several lines of clinical trials using NK(1) receptor antagonists have been conducted to date, and the efficiency of preclinical assessments for proof of concept and dose optimization could be greatly increased by configuring an in vivo analytical system that permits quantitative mapping of NK(1) receptors in the brains of small-size laboratory animals expressing "human-like" NK(1) receptors. Hence, we investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [(18)F]fluoroethyl-SPA-RQ, a modification of a recently established radioligand for NK(1) receptors. A pharmacokinetic assay could be performed for a rhesus monkey in an awake condition, which allows the circumvention of influences of anesthesia on SP neurotransmission. Coregistration of PET and magnetic resonance images acquired by small-animal-dedicated devices enabled detailed localization of NK(1) receptors in the gerbil and marmoset brains. The present study also revealed the potentials of SDZ NKT 343 as an antagonist for central NK(1) receptors. In conjunction with additional in vitro and ex vivo autoradiographic observations, our in vivo results have demonstrated a similarity in the binding pattern among the animals examined, justifying cross-species extrapolation of PET findings on the SP-NK(1) pathway.

Animals↗
PubMed2006

Peroxisome proliferator-activated receptor alpha protects against glomerulonephritis induced by long-term exposure to the plasticizer di-(2-ethylhexyl)phthalate.

Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator-activated receptor alpha (PPARalpha), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPARalpha mediates toxicity, wild-type and PPARalpha-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPARalpha-null mice that were exposed to DEHP exhibited prominent immune complex glomerulonephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPARalpha-dependent anti-inflammatory effects that normally antagonize the NFkappaB signaling pathway accompanied the glomerulonephritis in PPARalpha-null mice. The results reported here indicate that PPARalpha protects against the nephrotoxic effects of long-term exposure to DEHP.

Animals↗
PubMed2006

Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice.

The M5 muscarinic acetylcholine receptor (M5R) has been shown to play a crucial role in mediating acetylcholine-dependent dilation of cerebral blood vessels. We show that male M5R-/- mice displayed constitutive constriction of cerebral arteries using magnetic resonance angiography in vivo. Male M5R-/- mice exhibited a significantly reduced cerebral blood flow (CBF) in the cerebral cortex, hippocampus, basal ganglia, and thalamus. Cortical and hippocampal pyramidal neurons from M5R-/- mice showed neuronal atrophy. Hippocampus-dependent spatial and nonspatial memory was also impaired in M5R-/- mice. In M5R-/- mice, CA3 pyramidal cells displayed a significantly attenuated frequency of the spontaneous postsynaptic current and long-term potentiation was significantly impaired at the mossy fiber-CA3 synapse. Our findings suggest that impaired M5R signaling may play a role in the pathophysiology of cerebrovascular deficits. The M5 receptor may represent an attractive novel therapeutic target to ameliorate memory deficits caused by impaired cerebrovascular function.

Acetylcholine↗
PubMed2006

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins.

Because the deposition of beta-amyloid protein (Abeta) is a consistent pathological hallmark of Alzheimer's disease (AD) brains, inhibition of Abeta generation, prevention of Abeta fibril formation, or destabilization of preformed Abeta fibrils would be attractive therapeutic strategies for the treatment of AD. We examined the effects of several medicinal herbs used in traditional Chinese medical formulae on the formation and destabilization of Abeta fibrils by using the thioflavin T binding assay, atomic force microscopic imaging, and electrophoresis. Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively. Significant destabilization of preformed Abeta(1-40) and Abeta(1-42) fibrils was also induced by Uncaria rhynchophylla as well as some other herb extracts. Three-dimensional HPLC analysis indicated that the water extract of this herb contains several different chemical compounds, including oxindole and indol alkaloids, which have been regarded as neuroprotective. Our results suggest that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils, and we conclude that this medicinal herb could have the potency to be a novel therapeutic agent to prevent and/or cure AD.

Alzheimer Disease↗
PubMed2006

The role of extrastriatal dopamine D2 receptors in schizophrenia.

Despite numerous studies on extrastriatal regions involved in schizophrenia, studies on the functional implications of dopamine (DA) D2 receptors in the extrastriatal regions, including the cortex and thalamus, are limited. We review postmortem and in vivo human imaging studies as well as animal studies, focusing on the function of extrastriatal DA D2 receptors and their role in the pathophysiology of schizophrenia. Based on recent findings, cortical DA D2 receptors may interact with the gamma-aminobutyric acid system to modulate DA transmission, and thalamic DA D2 receptors are likely to participate in sensory gating function into the prefrontal cortex. We have found decreased DA D2 receptors in the anterior cingulate cortex and thalamic subregions of patients with schizophrenia. These observations may suggest that alterations of extrastriatal DA D2 receptors are involved in dysregulation of DA transmission and sensory signals from the thalamus to the cortex. Excessive excitatory signals from the thalamus might flow into the cortical neurotransmission system, aggravating dysregulation of DA transmission in both the striatal and extrastriatal regions in schizophrenia. These notions suggest the need for future investigations of extrastriatal DA D2 receptor function to gain important clues regarding the pathogenesis and of possible treatments for schizophrenia.

Brain↗
PubMed2006

Chronic inhibition of nitric oxide production aggravates diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats.

BACKGROUND: Nitric oxide (NO) is known to play a role in diabetic nephropathy, but the molecular basis for this effect remains unclear. METHOD: Otsuka Long-Evans Tokushima Fatty spontaneous diabetic rat models were used along with Long-Evans Tokushima Otuska rat models as age-matched controls. Either L-arginine (a NO precursor) or L-NAME (a nitric oxide synthase inhibitor) was administered from the age of 22 weeks. Clinical parameters and serum and urinary NO2+NO3 levels were measured, in addition to renal histological findings and ED-1-positive cell counts in glomeruli. RESULTS: There were no significant differences in creatinine clearance between any of the groups at any point. The levels of urinary NO2+NO3 in the diabetic group were significantly lower than those in the control groups after 40 weeks; that in the L-NAME diabetic group was significantly lower than in the other diabetic groups at 52 weeks. Compared with the other diabetic groups, the L-NAME diabetic group had significantly higher urinary protein excretion levels, histological scores, and numbers of ED-1-positive cells in glomeruli. Diabetic rats administered L-arginine excreted more urinary protein than the diabetic controls. CONCLUSION: Diabetic nephropathy was exacerbated drastically by a nitric oxide synthase inhibitor and mildly by a NO precursor. These data suggested that NO may modify type 2 diabetic nephropathy in Otuska Long-Evans Tokushima Fatty rats through factors other than hemodynamics.

Animals↗
PubMed2006

Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.

A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.

Alzheimer Disease↗
PubMed2006

Animal models of tauopathies.

Intracellular fibrillar amyloid lesions comprised of tau proteins are pathological hallmarks in diverse neurodegenerative disorders. As models of these tauopathies, transgenic mice overexpressing tau with or without mutations discovered in familial tauopathies were generated. Findings in these tau transgenic mice support the notion that impairments of tau proteins are causally related to tauopathies, while studies on crossbred mice have indicated initiation and promotion of tau-positive neuropathologies by crosstalk among several pathogenic molecules. Enhancement of tau pathology by amyloid beta (Abeta) deposition provided some of the most compelling evidence for such a cross-talk, and molecular processes linking abnormalities of Abeta and tan have been suggested to involve activation of calcium-dependent protease, calpain, based on analyses of amyloid precursor protein transgenic mice crossbred with other genetically engineered mice with altered calpain activity. It also should be noted that mice transgenic for both tau and alpha-synuclein exhibit facilitated polymerization of these molecules into pathological filaments. Roles of fibrillar tau deposits in nervous system injuries can be mechanistically pursued by longitudinal monitoring of brain amyloidosis and neuroglial degeneration in the time course of antiamyloid intervention. The possibility of in vivo detection of tau-positive amyloid lesions has been demonstrated by intravenous administration of potential tracers into tau transgenic mice and subsequent brain imaging. Moreover, visualization of glial responses in living brains may allow sensitive detection of degenerative changes in the central nervous system.

Animals↗
PubMed2006

[Imaging of glial cells by positron-emitted peripheral benzodiazepine receptor ligands].

Recently, it has been indicated that glial cells play as important role in the development of neurodegenerative disorders. Expression of peripheral benzodiazepine receptor (PBR) has higher localization in the glial cells than in the neural cells, and is a noticeable marker for gliosis produced by neurodegeneration. In vivo imaging of PBR has been attempted by [11C]PK11195 positron emission tomography (PET), and it has been documented that the [11C]PK11195 binding potential increases in various neurodegenerative disorders such as Alzheimer's disease and stroke. Furthermore, we have succeeded in developing new positron ligands [11C]DAA1106 and [18F]fluoroethyl-DAA1106 for visualization of PBRs, which have higher accumulation in the brain than [11C]PK11195. We concluded that PET imaging by PBR ligands is useful for diagnosis of neurodegenerative disorders.

Acetamides↗
PubMed2005

Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats.

We evaluated correlation between neurochemical and functional alterations of the nigrostriatal dopaminergic system in rat brains lesioned with 6-hydroxydopamine (6-OHDA), that model hemi-Parkinson's disease (PD), by using three different quantitative in vivo and in vitro methods. Rats unilaterally lesioned with different doses of 6-OHDA underwent two types of in vivo experiments: (1) a rotational behavioral study with methamphetamine (MAP) or apomorphine (APO); and (2) a positron emission tomography (PET) study with [11C]PE2I (radioligand for dopamine transporters) or [11C]raclopride (radioligand for dopamine D2 receptors). An in vitro autoradiographic study with the same radioligands was also conducted. The number of rotations after the MAP or APO injection increased with increased doses of 6-OHDA. The in vitro and in vivo binding of [11C]PE2I dose-dependently decreased in response to the 6-OHDA injections, while that of [11C]raclopride dose-dependently increased. There was a significant negative hyperbolic correlation between the number of rotations after MAP injection and the binding of [11C]PE2I. In contrast, there was a significant positive linear correlation between the number of rotations after APO injections and the binding of [11C]raclopride. These results robustly reveal a molecular pharmacological basis of parkinsonian symptoms in animal models of PD, and indicate the utility and validity of in vivo PET measurements in assessing pre- and post-synaptic dopaminergic functions.

Animals↗
PubMed2005

Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies.

Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data suggest that the accumulation of tau in OLG cause neurodegeneration, and we infer they do so by disrupting axonal transport. We suggest that similar defects may also occur in sporadic and hereditary human tauopathies with OLG tau pathologies.

Animals↗
PubMed2005

Pharmacokinetics and brain uptake of lactoferrin in rats.

Lactoferrin (Lf) is an iron-binding glycoprotein belonging to the transferrin (Tf) family. Lf was reported to cross the blood brain barrier (BBB) via receptor-mediated transcytosis in an in vitro model of the BBB. In the present study, we compared the in vivo brain uptake of Lf with that of OX26, an anti-Tf receptor antibody, and Tf. These three proteins were radiolabeled with 125I and administered to rats by i.v. injection. We found that Lf was more rapidly eliminated from the blood compared with OX26 and Tf (The half-life of Lf was approximately 8 and 6 times shorter than that of OX26 and Tf, respectively; the area under the blood concentration-time curve of Lf was approximately 15 and 17 times smaller than that of OX26 and Tf, respectively), and mainly accumulated in the liver, spleen, and kidney. Markedly high brain uptake was observed for Lf relative to Tf and OX26. Lf might be useful as a ligand for facilitating drug delivery into the brain.

Animals↗
PubMed2005

Metabolism of amyloid-beta peptide and Alzheimer's disease.

The accumulation of amyloid-beta peptide (Abeta), a physiological peptide, in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD) and appears to be caused by an increase in the anabolic activity, as seen in familial AD cases or by a decrease in catabolic activity. Neprilysin is a rate-limiting peptidase involved in the physiological degradation of Abeta in the brain. As demonstrated by reverse genetics studies, disruption of the neprilysin gene causes elevation of endogenous Abeta levels in mouse brain in a gene-dose-dependent manner. Thus, the reduction of neprilysin activity will contribute to Abeta accumulation and consequently to AD development. Evidence that neprilysin in the hippocampus and cerebral cortex is down-regulated with aging and from an early stage of AD development supports a close association of neprilysin with the etiology and pathogenesis of AD. Therefore, the up-regulation of neprilysin represents a promising strategy for therapy and prevention. Recently, somatostatin, which acts via a G-protein-coupled receptor (GPCR), has been identified as a modulator that increases brain neprilysin activity, resulting in a decrease of Abeta levels. Thus, it may be possible to pharmacologically control brain Abeta levels with somatostatin receptor agonists.

Alzheimer Disease↗
PubMed2005

Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.

Expression of somatostatin in the brain declines during aging in various mammals including apes and humans. A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease. Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid beta peptide (Abeta), the primary pathogenic agent of Alzheimer disease, in the brain through modulating proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons. A genetic deficiency of somatostatin altered hippocampal neprilysin activity and localization, and increased the quantity of a hydrophobic 42-mer form of Abeta, Abeta(42), in a manner similar to presenilin gene mutations that cause familial Alzheimer disease. These results indicate that the aging-induced downregulation of somatostatin expression may be a trigger for Abeta accumulation leading to late-onset sporadic Alzheimer disease, and suggest that somatostatin receptors may be pharmacological-target candidates for prevention and treatment of Alzheimer disease.

Aging↗
PubMed2005

Understanding molecular mechanisms of proteolysis in Alzheimer's disease: progress toward therapeutic interventions.

Amyloid beta peptide (Abeta) is not only a major constituent of extracellular fibrillary pathologies in Alzheimer's disease (AD) brains, but is also physiologically produced and metabolized in neurons. This fact led us to the notion that an age-related decrease in Abeta catabolism may contribute to the molecular pathogenesis of AD, providing a rationale for seeking proteolytic enzymes that degrade Abeta in the brain. Our recent studies have demonstrated that neprilysin is the most potent Abeta-degrading enzyme in vivo. Deficiency of endogenous neprilysin elevates the level of Abeta in brains of neprilysin-knockout mice in a gene dose-dependent manner, and an age-associated decline of neprilysin occurs in several regions of mouse brain. Neuropathological alterations in these same regions have been implicated in cognitive impairments of AD patients at an early stage of the disease. Furthermore, the level of neprilysin mRNA has been found to be significantly and selectively reduced in the hippocampus and temporal cortex of AD patients. A clarification of the role played by decreased neprilysin activity in the pathogenesis of AD has opened up the possibility of neprilysin up-regulation as a novel preventive and therapeutic approach to AD. Since the expression level and activity of neprilysin are likely to be regulated by neuropeptides and their receptors, non-peptidic agonists for these receptors might be effective agents to maintain a sufficient level of Abeta catabolism in brains of the elderly. In addition to Abeta deposits, intraneuronal fibrillary lesions, such as neurofibrillary tangles, are also a pathological hallmark of AD, and the extent of the resultant cytoskeletal disruptions may be dependent upon the activity levels of proteolytic enzymes. Among proteases for which major cytoskeletal components are good substrates, calpains were shown to participate in excitotoxic stress-induced neuritic degeneration in our recent analysis using genetically engineered mice. Moreover, we have found that this pathology can be reduced by controlling the activity of an endogenous calpain inhibitor known as calpastatin, providing a possible approach for the treatment of diverse neurodegenerative disorders, including AD.

Alzheimer Disease↗
PubMed2005

19F and 1H MRI detection of amyloid beta plaques in vivo.

Formation of senile plaques composed of amyloid beta peptide, a pathological hallmark of Alzheimer disease, in human brains precedes disease onset by many years. Noninvasive detection of such plaques could be critical in presymptomatic diagnosis and could contribute to early preventive treatment strategies. Using amyloid precursor protein (APP) transgenic mice as a model of amyloid beta amyloidosis, we demonstrate here that an intravenously administered (19)F-containing amyloidophilic compound labels brain plaques and allows them to be visualized in living mice by magnetic resonance imaging (MRI) using (19)F and (1)H. Our findings provide a new direction for specific noninvasive amyloid imaging without the danger of exposure to radiation. This approach could be used in longitudinal studies in mouse models of Alzheimer disease to search for biomarkers associated with amyloid beta pathology as well as to track disease course after treatment with candidate medications.

Age Factors↗
PubMed2005

Distinct mechanistic roles of calpain and caspase activation in neurodegeneration as revealed in mice overexpressing their specific inhibitors.

Enzymatic proteolysis has been implicated in diverse neuropathological conditions, including acute/subacute ischemic brain injuries and chronic neurodegeneration such as Alzheimer disease and Parkinson disease. Calcium-dependent proteases, calpains, have been intensively analyzed in relation to these pathological conditions, but in vivo experiments have been hampered by the lack of appropriate experimental systems for a selective regulation of the calpain activity in animals. Here we have generated transgenic (Tg) mice that overexpress human calpastatin, a specific and the only natural inhibitor of calpains. In order to clarify the distinct roles of these cell death-associated cysteine proteases, we dissected neurodegenerative changes in these mice together with Tg mice overexpressing a viral inhibitor of caspases after intrahippocampal injection of kainic acid (KA), an inducer of neuronal excitotoxicity. Immunohistochemical analyses using endo-specific antibodies against calpain- and caspase-cleaved cytoskeletal components revealed that preclusion of KA-induced calpain activation can rescue the hippocampal neurons from disruption of the neuritic cytoskeletons, whereas caspase suppression has no overt effect on the neuritic pathologies. In addition, progressive neuronal loss between the acute and subacute phases of KA-induced injury was largely halted only in human calpastatin Tg mice. The animal models and experimental paradigm employed here unequivocally demonstrate their usefulness for clarifying the distinct contribution of calpain and caspase systems to molecular mechanisms governing neurodegeneration in adult brains, and our results indicate the potentials of specific calpain inhibitors in ameliorating excitotoxic neuronal damages.

Animals↗