Stimulation tests of human growth hormone secretion by insulin, lysine vasopressin, pyrogen and glucagon

Firstly, comparisons have been made of the secretion of human growth hormone (HGH) that was induced by insulin, lysine vasopressin and pyrogen injections in order to study whether these substances can be utilized as a rapid test of HGH secretion. In insulin test, a fall of the fasting blood glucose level by 28.6% or more seemed to be sufficient to provoke adequate HGH elevation, and 9.4 ng/ml or higher HGH increment was recognized as being normal, because lysine vasopressin and pyrogen produce varying degrees of side-effects and are less specific and unpredictable in the release of HGH. Secondly, the pharmacologic effects and mechanism of action of exogenous glucagon upon the HGH secretion were studied. In normal subjects after one mg sc glucagon, there was a mean peak blood glucose level of 142. 4±3.l mg/lOO ml at 30 min, HGH levels reached a mean peak level of 22. 6±4. 8 ng/ml at 150 min, and no false negative response was noted. In patients with hypopituitarism, there was no positive response in plasma HGH levels after the sc glucagon. The present study revealed that the rise and subsequent fall of blood glucose are not the sole mechanism responsible for the effct of glucagon on HGH secretion, and that the HGH secretion in response to the sc glucagon was not triggered by cathecholamine via the stimulation of the adrenal medulla.</p

Possible Neuroprotective Therapy for Parkinson's Disease

Neuroprotective therapy for Parkinson's disease (PD) is a treatment intended to prevent or reduce neuronal degeneration. Since clinical studies to evaluate such an effect would be prolonged, the choice of agents for use as possible neuroprotective therapy is based on the results of in vitro and animal experiments. Free radicals are currently regarded as the most important factor in the progression of PD. One current possible neuroprotective therapy is reduction of levodopa dose, since levodopa is a source of free radical formation. Dopamine (DA) metabolism inhibition, and administration of the DA agonist bromocriptine that eliminates hydroxyl free radicals have neuroprotective effects experimentally. The other candidates for neuroprotective agents are still under development. However, those whose clinical use is permitted should be considered for use, since patients with long-standing PD cannot wait until the neuroprotective efficacy of these agents is confirmed by clinical study.</p

Factors affecting levodopa effects in Parkinson's disease.

Levodopa is the gold standard for the treatment of Parkinson's disease (PD) because of its outstanding clinical efficacy. However, the majority of patients experience various adverse reactions, including the wearing-off phenomenon, the on-off phenomenon, dyskinesia and psychiatric symptoms. The response to levodopa depends not only on the intrinsic responsiveness of the patients, but also on various other important factors including the type of levodopa preparation, its absorption/metabolism, the blood-brain barrier, age at onset of disease and concomitant use of anti-parkinsonian drugs. This review summarizes factors which influence the effects of levodopa in PD. To minimize levodopa-induced adverse reactions and to relieve long-term parkinsonian symptoms, levodopa therapy should be conducted by taking these factors into consideration.</p

Neuropeptides and their receptors in aged-rat brain.

Age-associated changes in methionine-enkephalin (ENK) and thyrotropin releasing hormone (TRH) concentrations, and their receptors were examined in discrete regions of the rat brain. The ENK and TRH concentrations in aged rats were nearly identical to those in young adult rats, except for a slightly lower TRH value in the hypothalamus of the aged rats. On the other hand, the ENK and TRH receptor levels in the cerebral cortex of aged rats was markedly lower than that of young adults rats. The results suggest that determinations of both neuropeptide and receptor levels are indispensable for evaluation of peptide-mediated neural systems in the central nervous system.</p

Molecular and chemical neuropharmacology of dopamine receptor subtypes

In the fields of psychiatry and neurology, the dopaminergic system is one of the most important neurotransmitter systems in the brain. Whereas pharmacological and biochemical studies had initially indicated two subclasses of dopamine receptors (DA-R), recent progress in molecular biology techniques has led to the identification of five distinct genes of DA-Rs (D1-R-D5-R) and splice variants. The gene products are classified into the D1-R family (D1-R and D5-R) and D2-R family (D2-R, D3-R and D4-R) based on their structure and pharmacological features. This review summarizes the structure, localization, function and pharmacology of DA-R subtypes on the basis of knowledge obtained during the past few years. The genes encoding the D1-R family have no intron and the D2-R family genes have introns. The distributions of mRNAs encoding these five DA-R subtypes in the brain were different from their respective receptors. The localization of DA-R subtypes to particular brain regions and specific pharmacological profiles of DA-R subtypes allow new insights to be made into the mechanism of action of DA in the control of psychiatric and motor functions. The availability of detailed information about DA-R subtypes will not only clarify their roles in the brain, but will probably also lead to the development of new therapeutic drugs with more specific actions.</p

Inhibitory effects of glucocorticoids on prolactin release induced by thyrotropin-releasing hormone in man

Glucocorticoid effect on thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) release was studied in female patients with collagen or autoimmune diseases. Long-term, high dose glucocorticoid therapy tended to inhibit the response of plasma PRL to TRH. A negative correlation (r=-0.40) was found between the logarithm of total dose of glucocorticoids received and the magnitude of plasma PRL response to TRH (p less than .05).</p

Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuron-specific degeneration in the substantia nigra. A number of gene mutations and deletions have been reported to play a role in the pathogenesis of familial PD. Moreover, a number of pathological and pharmacological studies on sporadic PD and dopaminergic neurotoxin-induced parkinsonism have hypothesized that mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system all play important roles in the pathogenesis and progress of PD. However, these hypotheses do not yet fully explain the mechanisms of dopaminergic neuron-specific cell loss in PD. Recently, the neurotoxicity of dopamine quinone formation by auto-oxidation of dopamine has been shown to cause specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and dopaminergic neurotoxin-induced parkinsonism. Furthermore, this quinone formation is closely linked to other representative hypotheses in the pathogenesis of PD. In this article, we mainly review recent studies on the neurotoxicity of quinone formation as a dopaminergic neuron-specific oxidative stress and its role in the etiology of PD, in addition to several neuroprotective approaches against dopamine quinone-induced toxicity.</p

Clinical applications of neurotransmitter-receptor studies in geriatric neuropharmacology.

The use of ligand-binding methods to study neurotransmitter-receptor sites has made its impact on almost all aspects of biological pursuits including research on aging and neurodegenerative diseases. In the past, most of the research in biochemical gerontology has largely centered around changes in various neurotransmitters and enzymatic activities. The molecular basis of aging and neurodegeneration at the level of neurotransmitter-receptor interactions has been highly appreciated in the last two decades as a result of receptor binding studies. It is now possible to obtain information about the regional distribution of neurotransmitter receptors in the brain, the pharmacological and biochemical characteristics of these sites, and the functional interrelationships between different neuronal systems in normal and pathological conditions. The passage of time after maturity is accompanied by measurable physiologic decline in virtually all systems. It is the aim of this work to discuss the practical aspects of neurotransmitter and/or drug (ligand)-receptor binding studies, highlighting some examples of their applications to geriatric neuropharmacology research, with special consideration to learning impairment and memory loss in normal and in pathological aging processes.</p

Involvement of STAT3 in Bladder Smooth Muscle Hypertrophy Following Bladder Outlet Obstruction

We examined the involvement of the signal transducer and activator of transcription 3 (STAT3) in bladder outlet obstruction (BOO)-induced bladder smooth muscle hypertrophy using a rat in vivo and in vitro study. BOO induced increases in bladder weight and bladder smooth muscle thickness 1 week after the operation. By using antibody microarrays, 64 of 389 proteins blotted on the array met our selection criteria of an INR value between > or = 2.0 and < or = 0.5. This result revealed up-regulation of transcription factors, cell cycle regulatory proteins, apoptosis-associated proteins and so on. On the other hand, down-regulation (INR value < or = 0.5) of proteins was not found. In a profiling study, we found an increase in the expression of STAT3. A significant increase in nuclear phosphorylated STAT3 expression was confirmed in bladder smooth muscle tissue by immunohistochemistry and Western blot analysis. Cyclical stretch-relaxation (1 Hz) at 120% elongation significantly increased the expression of STAT3 and of alpha-smooth muscle actin in primary cultured bladder smooth muscle cells. Furthermore, the blockade of STAT3 expression by the transfection of STAT3 small interfering RNA (siRNA) significantly prevented the stretch-induced increase in alpha-smooth muscle actin expression. These results suggest that STAT3 has an important role in the induction of bladder smooth muscle hypertrophy

Optimization of permanent magnet type of retarder using 3-D finite element method and direct search method

3-D optimization method using the combined experimental design method and direct search method is developed to apply to the optimal design of a permanent magnet type of retarder. It is shown that the braking torque is increased by using the optimization method. The CPU time can be considerably reduced by utilizing the initial values obtained by the experimental design method </p