Effect of chloroquine-induced myopathy on rat soleus muscle sarcoplasm and expression of clathrin

Clathrin-coated vesicles are involved in receptor-mediated intracellular transport pathways related to lysosomal proteolysis. Clathrin levels were significantly elevated in denervated soleus muscles from chloroquine- and saline-treated rats as compared with their contralateral, innervated muscles. No difference was found in the clathrin levels of the denervated muscles in both groups. The accumulation of autophagic vacuoles was marked only in chloroquine-treated muscles after denervation. These findings suggest that chloroquine does not inhibit intracellular trafficking of clathrin-coated vesicles during the overdevelopment of autophagic vacuoles. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:665–668, 1998.     

Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor

Analyses were performed to evaluate the roles of the beta1- and beta2-adrenergic receptors in the skeletal muscle hypertrophy and anti-atrophy response to the beta-adrenergic agonist, clenbuterol. Treatment of wild-type mice with clenbuterol resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. Treatment of beta1-adrenergic receptor knockout mice with clenbuterol also resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. In contrast, in beta2-adrenergic receptor knockout mice and in mice lacking both the beta1- and beta2-adrenergic receptors, clenbuterol treatment did not result in hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles, nor did it inhibit denervation-induced atrophy in these muscles. Together these data demonstrate that the beta2-adrenergic receptor is responsible for both the skeletal muscle hypertrophy and anti-atrophy effects of the beta-adrenergic agonist clenbuterol.     

Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats

Five N-methyl-D-aspartate (NMDA) receptor subunits have been identified thus far: NR1, NR2A, NR2B, NR2C, and NR2D. Here, we have analyzed the expression patterns of mRNAs for the NMDA receptor subunits in the developing and adult rats by in situ hybridization. The developmental changes of the expression patterns were most salient in the cerebellum. In the external granular layer, hybridization signals of mRNAs, for NR1, NR2A, NR2B, and NR2C appeared by postnatal day 3, but no NR2D mRNA was expressed at any developmental stage examined. The NR1 mRNA was expressed in all cerebellar neurons at all developmental stages examined. The signals for the NR2A mRNA appeared in Purkinje cells and granule cells during the second postnatal week. The signals for the NR2B mRNA in granule cells were seen transiently during the first 2 weeks after birth. The signals for NR2C mRNA appeared in granule cells and glial cells during the second postnatal week. The signals for NR2D mRNA appeared transiently in Purkinje cells during the first 8 postnatal days; in adult rats, these were seen in stellate and Golgi cells. In the cerebellar nuclei, mRNAs for NR1, NR2A, NR2B, and NR2D were more or less expressed on postnatal day 0, while expression signals for the NR2C mRNA were first detected in postnatal day 14. Thus, the most conspicuous changes of expression patterns were observed in the cerebellar cortex during the first 2 weeks after birth, when development and maturation of the cerebellum proceed most rapidly. © 1994 Wiley-Liss, Inc.     

Role of ubiquitin–proteasome proteolysis in muscle fiber destruction in experimental chloroquine‐induced myopathy

Previous studies have documented the presence of rimmed vacuoles, atrophic fibers, and increased lysosomal cathepsin activity in skeletal muscle from animal models of chloroquine‐induced myopathy, suggesting that muscle fibers in this type of myopathy may be degraded via the lysosomal‐proteolysis pathway. Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, in this study we chose to examine the significance of the ubiquitin–proteasome proteolytic system in the process of muscle fiber destruction in experimental chloroquine myopathy. Expression of ubiquitin, 26S proteasome proteins, and ubiquitin ligases, such as muscle‐specific RING finger‐1 (MuRF‐1) and atrogin‐1/muscle atrophy F‐box protein (MAFbx), was analyzed in innervated and denervated rat soleus muscles after treatment with either saline or chloroquine. Abnormal accumulation of rimmed vacuoles was observed only in chloroquine‐treated denervated muscles. Ubiquitin and proteasome immunostaining, and ubiquitin, MuRF‐1, and atrogin‐1/MAFbx mRNAs were significantly increased in denervated soleus muscles from saline‐ and chloroquine‐treated rats when compared with contralateral innervated muscles. Further, ubiquitin and ubiquitin ligase mRNA levels were higher in denervated muscles from chloroquine‐treated rats when compared with saline‐treated rats. These data demonstrate increased proteasomes and ubiquitin in denervated muscles from chloroquine‐treated rats and suggest that the ubiquitin–proteasome proteolysis pathway as well as the lysosomal‐proteolysis pathway mediate muscle fiber destruction in experimental chloroquine myopathy. Muscle Nerve 39: 521–528, 2009     

NMDA-NR1 receptor subunit mRNA expression in rat brain after 6-OH-dopamine induced lesions: A non-isotopic in situ hybridization study

Antisense digoxigenin-labeled deoxyoligonucleotides probes and non-isotopic in situ hybridization (HIS) techniques have been used to explore the NMDA-NR1 receptor subunit mRNA distribution in different brain areas of rats which had their dopaminergic nigrostriatal pathway previously lesioned with intracerebral administration of 6-OH-dopamine (6-OH-DA). Intense and significant hybridization signals for NR1 mRNA were found in dentate gyrus and regions CA₁-CA₂-CA₃ of the hippocampus, in layers II-III and V-VI of the cerebral cortex, and in the cerebellum of sham-treated rats. Basal ganglia structures such as the striatum exhibited few NR1 mRNA hybridization signals as compared to the hippocampus and cerebral cortex. In contrast, both zona compacta and reticulata of substantia nigra (SN) showed a reduced number of cells with nevertheless intense NR1 mRNA HIS signals. The NR1 mRNA distribution in the brain was affected in a brain regional selective manner by 6-OH-DA induced lesions of DA neuronal systems. A striking increase in NR1 mRNA HIS signals was observed in both striata after unilateral lesioning with 6-OH-DA. Instead, in SN compacta but not in reticulata, a moderate but significant bilateral reduction of NR1 mRNA was observed after unilateral 6-OH-DA injection. No significant changes in NR1 mRNA were detected in cerebral cortex and other brain regions after 6-OH-DA treatment. These studies, and others reported in the literature, support the view that extensive lesions of nigrostriatal DA-containing neurons in the brain may trigger compensatory or adaptative responses in basal ganglia structures such as striatum and substantia nigra which involve glutamatergic neurons and the genic expression of NMDA receptors. © 1996 Wiley-Liss, Inc.     

Neural regulation of glucose 6-phosphate dehydrogenase in rat muscle: effect of denervation and reinnervation

We tested the hypothesis that glucose 6-phosphate dehydrogenase (G6PD) in rat extensor digitorum longus (EDL) muscle is under neural control by studying changes in G6PD activity in EDL muscles following nerve crush-induced denervation and reinnervation. Changes in G6PD were correlated with choline acetyltransferase activity, as well as with neurological function, muscle weights, and muscle isometric twitch tension. The data show a dramatic increase in G6PD following denervation. The gradual recovery of enzyme activity toward normal levels correlates with the return of functional synaptogenesis manifested by the return of neurological function, choline acetyltransferase, and muscle twitch tension. We conclude, therefore, that muscle G6PD is under neural control. G6PD activity provides a facile biochemical indicator of muscle reinnervation.     

Role of interleukin‐6 and soluble IL‐6 receptor in region‐specific induction of astrocytic differentiation and neurotrophin expression

Increasing evidence supports an essential role for interleukin‐6 (IL‐6) in the development, differentiation, as well as de‐ and re‐generation of neurons in the central nervous system (CNS). Both IL‐6 and its specific receptor (IL‐6R) are expressed on neurons and glial cells including astrocytes. In this study, we have analyzed the responses of primary rat astrocytes of various brain regions to IL‐6 with respect to morphological changes and neurotrophin expression. Since IL‐6 alone failed to initiate effects on astrocytes, we have examined whether the soluble IL‐6R (sIL‐6R) can modulate the responsiveness of to IL‐6 in these cells. For this purpose, we used a highly active fusion protein of IL‐6 and sIL‐6R, which is designated Hyper‐IL‐6 (H‐IL‐6). We show that treatment of cultured astrocytes with Hyper‐IL‐6 promotes region‐specific morphological changes of GFAP‐positive astrocytes from typical stellate‐ to fibrous‐like cells. In addition, we find that Hyper‐IL‐6 induces expression of neurotrophins (NTs) of the nerve growth factor (NGF)‐family in a dose‐dependent manner. Interestingly, astrocytes of various brain regions show differing patterns of cytokine‐induced NT expression: NGF is maximally induced in cortex and hippocampus, NT‐3 in hippocampus, and NT‐4/5 in cortex and cerebellum. In summary, our results indicate that IL‐6 in conjunction with sIL‐6R regulates specific neurotrophin expression in astrocytes in a brain region dependent manner. Thus, the IL‐6 system provides a local supply of neurotrophins that participate in diverse CNS functions such as protection of neurons from insults, neuronal survival, and neuro‐immune responses. GLIA 26:191–200, 1999. © 1999 Wiley‐Liss, Inc.     

Insulin-like growth factor-II/Mannose-6-phosphate receptor in the spinal cord and dorsal root ganglia of the adult rat

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional transmembrane glycoprotein, which interacts with a number of molecules, including IGF-II and M6P-containing lysosomal enzymes. The receptor is widely distributed throughout the brain and is known to be involved in lysosomal enzyme trafficking, cell growth, internalization and degradation of IGF-II. In the present study, using autoradiographic, Western blotting and immunocytochemical methods, we provide the first report that IGF-II/M6P receptors are discretely distributed at all major segmental levels of the spinal cord and dorsal root ganglia of the adult rat. In the spinal cord, a high density of [(125)I]IGF-II binding sites was evident in the ventral horn (lamina IX) and in areas around the central canal (lamina X), whereas intermediate grey matter and dorsal horn were associated with moderate receptor levels. The dorsal root ganglia exhibited rather high density of [(125)I]IGF-II binding sites. Interestingly, meninges present around the spinal cord displayed highest density of [(125)I]IGF-II binding compared to any given region of the spinal grey matter or the dorsal root ganglia. Western blot results indicated the presence of the IGF-II/M6P receptor at all major levels of spinal cord and dorsal root ganglia, with little segmental variation. At the cellular level, spinal motorneurons demonstrated the most intense IGF-II/M6P receptor immunoreactivity, followed by interneurons in the intermediate region and deeper dorsal horn. Some scattered IGF-II/M6P immunoreactive fibers were found in the superficial laminae of the dorsal horn and dorsolateral funiculus. The meninges of the spinal cord also seemed to express IGF-II receptor immunoreactivity. In the dorsal root ganglia, receptor immunoreactivity was evident primarily in a subset of neurons of all diameters. These results, taken together, provide anatomical evidence of a role for the IGF-II/M6P receptor in general cellular functions such as transport of lysosomal enzymes and/or internalization followed by clearance of IGF-II in the spinal cord and dorsal root ganglia.     

Krebs von den Lungen 6 decreased in the serum and muscle of GNE myopathy patients

UDP‐N‐acetylglucosamine 2‐epimerase/N‐acetylmannosamine kinase (GNE) is necessary for sialic acid biosynthesis. GNE myopathy is caused by a defect in GNE, and hyposialylation is a key factor in the pathomechanism of GNE myopathy. Although candidates for evaluating hyposialylation have been reported, it is difficult to measure them in routine clinical practice. Sialylation is necessary for synthesis of various glycoproteins, including Krebs von den Lungen‐6 (KL‐6)/mucin 1 (MUC1). Here we report that KL‐6/MUC1 is decreased in GNE myopathy. We observed that KL‐6 levels were decreased in the serum of patients with GNE myopathy, and that KL‐6 and MUC1‐C were also decreased in muscle biopsy specimens from these patients. An immunofluorescent study revealed that KL‐6 and MUC1‐C were not present in the sarcolemma but were, instead, localized in rimmed vacuoles in specimens from patients with GNE myopathy. KL‐6 is already used to detect lung diseases in clinical practice, and this glycoprotein may be a novel candidate for evaluating hyposialylation in GNE myopathy.     

Subunit- and brain region-specific reduction of GABAA receptor subunit mRNAs during chronic treatment of rats with diazepam

The mRNA levels for several GABA_A receptor subunits were measured by Northern blot analysis. Rats were treated for 3 wk by continuous release of diazepam (DZP) from subcutaneous reservoirs, and then sacrificed immediately or 48 h after removing the reservoirs. Poly(A)⁺ RNAs, isolated from cerebral cortex, cerebellum, and hippocampus, were hybridized with oligonucleotide probes for GABA_A receptor subunits and a cDNA probe for β-actin. Subunit mRNAs were expressed relative to the corresponding β-actin mRNA. DZP treatment decreased the α₁ subunit mRNA level 40% in hippocampus, but it was not changed in cortex or cerebellum. The α₅ subunit mRNA level was decreased in cerebral cortex (28%) and hippocampus (15%). The γ₂ subunit mRNA level was decreased (40%) only in cortex. DZP treatment did not affect α₂, α₃, α₄, β₂, or β₃ subunit mRNA levels. Decreases in mRNA levels had reversed within 48 h after stopping chronic treatment. Acute DZP did not change α₁, α₅, or γ₂ subunit mRNA levels. The decreases in GABA_A receptor subunit mRNA levels were specific to subunit and brain region. These results, coupled with those after chronic flurazepam treatment, also indicated that the effects on GABA_A receptor subunit mRNA levels are specific to the benzodiazepine (BZ) used for chronic treatment.     

难治性颞叶癫痫脑组织IL-6、IL-6受体及sIL-6R、 sgp130的表达及意义

目的 探讨IL-6、IL-6膜受体(IL-6R)及其下游信号转导相关分子在颞叶癫痫(TLE)发生中的作用. 方法 选择自2010年1月至2010年12月在第三军医大学新桥医院神经外科行手术治疗的TLE患者40例(TLE组),同期行手术治疗的外伤、高血压脑出血等患者40例(对照组);收集其手术过程中切除的颞叶组织.利用RT-PCR、ELISA等方法分析IL-6、IL-6R、sIL-6R以及sgp130的mRNA或蛋白水平的表达变化情况. 结果 TLE组和对照组中均可检测到IL-6和IL-6R mRNA的表达,但TLE组致病灶中IL-6和IL-6R mRNA水平均显著高于对照组,差异有统计学意义(P＜0.05).ELISA结果提示,sIL-6R在TLE组致痫灶中的表达量与对照组比较明显增高,差异有统计学意义(P＜0.05);sgpl30的含量略高于对照组,差异没有统计学意义(P＞0.05). 结论 局部高浓度的IL-6通过经典信号转导或者跨信号转导机制作用于TLE病灶细胞,影响这些细胞的生物学功能,参与癫痫发生过程.     

Dopamine and N-methyl-D-aspartate receptor expression in peripheral blood of patients undergoing alcohol withdrawal

Summary The aim of the present pilot study was to explore whether a change in cerebral receptors can be demonstrated in human peripheral blood lymphocytes during alcohol withdrawal. Dopamine (D1 and D2) and NMDA (1 and 2B) receptor expressions of 14 male patients suffering from alcohol-dependency were assessed through quantitative RT-PCR. A significant difference in D1 receptor expression (T = 2.361; p = 0.035) in terms of up-regulation could be shown, though there were no significant changes concerning D2, NMDA1 or NMDA2B receptor expression. First two authors contributed equally     

Insulin-like growth factor-II/mannose-6-phosphate receptor: widespread distribution in neurons of the central nervous system including those expressing cholinergic phenotype

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is single transmembrane glycoprotein that plays a critical role in the trafficking of lysosomal enzymes and the internalization of circulating IGF-II. At present, there is little information regarding the cellular distribution of the IGF-II/M6P receptor within the adult rat brain. With the use of immunoblotting and immunocytochemical methods, we found that the IGF-II/M6P receptor is widely but selectively expressed in all major brain areas, including the olfactory bulb, striatum, cortex, hippocampus, thalamus, hypothalamus, cerebellum, brainstem, and spinal cord. Intense IGF-II/M6P receptor immunoreactivity was apparent on neuronal cell bodies within the striatum, deeper layers (layers IV and V) of the cortex, pyramidal and granule cell layers of the hippocampal formation, selected thalamic nuclei, Purkinje cells of the cerebellum, pontine nucleus and motoneurons of the brainstem as well as in the spinal cord. Moderate neuronal labeling was evident in the olfactory bulb, basal forebrain areas, hypothalamus, superior colliculus, midbrain areas, granule cells of the cerebellum and in the intermediate regions of the spinal gray matter. We also observed dense neuropil labeling in many regions, suggesting that this receptor is localized in dendrites and/or axon terminals. Double-labeling studies further indicated that a subset of IGF-II/M6P receptor colocalizes with cholinergic cell bodies and fibers in the septum, striatum, diagonal band complex, nucleus basalis, cortex, hippocampus, and motoneurons of the brainstem and spinal cord. The observed widespread distribution and colocalization of IGF-II/M6P receptor in the adult rat brain provide an anatomic basis to suggest a multifunctional role for the receptor in a wide-spectrum of central nervous system neurons, including those expressing a cholinergic phenotype.     

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.     

Anticonvulsant effect of a ghrelin receptor agonist in 6Hz corneally kindled mice

Ghrelin has anticonvulsant and neuroprotective effects in models of chemoconvulsant‐induced seizures and status epilepticus. In this study we investigated whether deletion of the ghrelin receptor could alter the kindling process in the 6 Hz corneal kindling model and whether ghrelin receptor ligands possess anticonvulsant effects in fully kindled mice. Ghrelin receptor wild‐type and knockout mice were electrically stimulated at a subconvulsive current twice daily via corneal electrodes until they reached the fully kindled state. Mice lacking the ghrelin receptor showed similar seizure severity during kindling acquisition as well as in the maintenance phase when compared to their wild‐type littermates. Subsequently we proceeded by investigating possible anticonvulsant effects of the ghrelin receptor ligands in the acute 6 Hz seizure model and the fully 6 Hz kindled mice. The ghrelin receptor agonist JMV‐1843 decreased the seizure severity score both in acutely 6 Hz stimulated mice and in fully kindled ghrelin receptor wild‐type mice, but not in fully kindled ghrelin receptor knockout mice. No effect on seizure severity was observed following the ghrelin receptor antagonist JMV‐2959 in both models. This finding indicates that JMV‐1843 exerts an anticonvulsant effect in kindled mice via the ghrelin receptor.     

Impaired expression of insulin-like growth factor-1 system in skeletal muscle of amyotrophic lateral sclerosis patients

Introduction:

Adult muscle fibers are a source of growth factors, including insulin‐like growth factor‐1 (IGF‐1). These factors influence neuronal survival, axonal growth, and maintenance of synaptic connections.

Methods:

We investigated the components of the IGF system in skeletal muscle samples obtained from 17 sporadic amyotrophic lateral sclerosis patients (sALS) and 29 control subjects (17 with normal muscle and 12 with denervated muscle unrelated to ALS).

Results:

The muscle expression of IGF‐1 and IGF‐binding proteins 3, 4, and 5 (IGF‐BP3, ‐4, and ‐5, respectively), assessed by immunohistochemistry, was differently decreased in sALS compared with both control groups; conversely, IGF‐1 receptor β subunit (IGF‐1Rβ) was significantly increased. Western blot analysis confirmed the severe reduction of IGF‐1, IGF‐BP3, and ‐BP5 with the increment of IGF‐1Rβ in sALS.

Conclusion:

In this study we describe the abnormal expression of the IGF‐1 system in skeletal muscle of sALS patients that could participate in motor neuron degeneration and should be taken into account when developing treatments with IGF‐1. Muscle Nerve, 2012     

5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585

The 5-hydroxytryptamine (5-HT; serotonin)-6 receptor (5-HT6R) is a putative target of atypical antipsychotic drugs and its mRNA expression is altered in schizophrenia. [125I]SB-258585 is a selective 5-HT6R antagonist which has been well characterized for use in the rat brain. The present study evaluated its suitability for receptor autoradiography in the human brain and its application to quantitative studies. The affinity (K(d) approximately 1.2 nM) and relative distribution of binding sites (striatum > cortex approximately hippocampus) were similar to the rat. The distribution of [125I]SB-258585 binding in these regions was also consistent with that of 5-HT6R mRNA, determined in parallel using in situ hybridization. [125I]SB-258585 binding site densities were measured in dorsolateral prefrontal cortex of 20 patients with chronic schizophrenia and compared with 17 normal subjects. No differences were seen between groups. Neither were [125I]SB-258585 binding site densities affected in the frontal cortex or striatum of rats following 2 weeks' administration of the antipsychotic drugs haloperidol, chlorpromazine, olanzapine, risperidone, or clozapine. In summary, [125I]SB-258585 is a suitable radioligand for studies of human brain 5-HT6R binding sites and shows that their distribution is broadly similar to that of the rodent. The lack of effect of schizophrenia or antipsychotic drug administration on [125I]SB-258585 binding suggests that an altered receptor density does not contribute to any involvement which the 5-HT6R may have in the disease or its treatment.     

The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional single transmembrane glycoprotein which, along with the cation-dependent M6P (CD-M6P) receptor, mediates the trafficking of M6P-containing lysosomal enzymes from the trans-Golgi network (TGN) to lysosomes. Cell surface IGF-II/M6P receptors also function in the degradation of the non-glycosylated IGF-II polypeptide hormone, as well as in the capture and activation/degradation of extracellular M6P-bearing ligands. In recent years, the multifaceted role of the receptor has become apparent, as several lines of evidence have indicated that in addition to its role in lysosomal enzyme trafficking, clearance and/or activation of a variety of growth factors and endocytosis-mediated degradation of IGF-II, the IGF-II/M6P receptor may also mediate transmembrane signal transduction in response to IGF-II binding under certain conditions. However, very little is known about the physiological significance of the receptor in the function of the central nervous system (CNS). This review aims to delineate what is currently known about IGF-II/M6P receptor structure, its ligand binding properties and role in lysosomal enzyme transport. It also summarizes the recent data regarding the role of the receptor in the CNS, including its distribution, possible importance for normal and activity-dependent functioning as well as its implications in neurodegenerative disorders such as Alzheimer's disease (AD).     

Sexually dimorphic expression of sst1 and sst2 somatostatin receptor subtypes in the arcuate nucleus and anterior pituitary of adult rats

The pattern of growth hormone (GH) secretion and rate of somatic growth are markedly sexually dimorphic, but the underlying neuroendocrine mechanisms are far from clear. In the present study, we tested the hypothesis that the sexual dimorphism of GH secretion may be due to gender-related differences in the transduction of somatostatin's actions in brain and/or pituitary. To accomplish this, we compared the distributional pattern and level of expression of two somatostatin receptor subtypes, sst1 and sst2, in the brain and pituitary of adult male and female rats by in-situ hybridization using 35S-labelled antisense riboprobes. In the brain, the hybridization pattern and labelling density of sst1 and sst2 mRNA-expressing cells, as revealed by computer-assisted image analysis, in areas including the cerebral cortex, medial habenula (MHb) and ventromedial hypothalamic nucleus (VMN), were similar in male and female rats. In contrast, there was a marked sex-related difference in sst1 expression in the arcuate nucleus of the hypothalamus; both the number and labelling density of sst1 mRNA-expressing cells were two- to threefold greater in males than in females and this significant increase was homogenous throughout the rostrocaudal extent of the nucleus. No gender-related differences in arcuate sst2 mRNA levels were found. At the level of the anterior pituitary, the labelling density of sst2 mRNA in males was significantly higher than that of females. No sex-related difference in pituitary sst1 mRNA was observed. These results demonstrate a sexual dimorphism in the expression of two somatostatin receptor subtypes, sst1 and sst2, at the level of the arcuate nucleus and anterior pituitary, respectively. Such dimorphism suggests a differential involvement of sst1 and sst2 in GH regulation with respect to gender, and may imply roles for sst2 and sst1 in transducing somatostatin's actions on pituitary somatotrophs and GH-releasing hormone-containing arcuate neurones, respectively, to generate the lower basal and higher GH pulse levels characteristic of the male rat.