Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Somatostatin (SRIF) exerts diverse physiological actions in the body including regulation of hormone and neurotransmitter release and neuronal firing activity. Analogs of SRIF are used clinically to treat tumors and cancers and to block the hypersecretion of growth hormone in acromegaly. 2. The recent cloning of five SRIF receptor subtypes has allowed for the identification of the molecular basis of the cellular actions of SRIF. The ligand binding domains and regions involved in coupling to G proteins and cellular effector systems are being identified and the processes by which SRIF inhibits cell growth and proliferation are being established. Furthermore, subtype selective agonists have been generated which are being used to investigate the specific biological roles of each SRIF receptor subtypes. 3. Such information will be useful in developing a new generation of SRIF drugs that could be employed to treat metabolic diseases, disorders of the gut, cancer and abnormalities in the central nervous system such as epilepsy and Alzheimer's disease.
Cell Mol Neurobiol 1995 Dec
PMID:Somatostatin. 871 32

1. The hippocampus is an important brain structure for working and spatial memory in animals and humans, and it is also a vulnerable as well as plastic brain structure as far as sensitivity to epilepsy, ischemia, head trauma, stress, and aging. 2. The hippocampus is also a target brain area for the actions of hormones of the steroid/thyroid hormone family, which traditionally have been thought to work by regulating gene expression. "Genomic" actions of steroid hormones involve intracellular receptors, whereas "nongenomic" effects of steroids involve putative cell surface receptors. Although this distinction is valid, it does not go far enough in addressing the variety of mechanisms that steroid hormones use to produce their effects on cells. This is because cell surface receptors may signal changes in gene expression, while genomic actions sometimes affect neuronal excitability, often doing so quite rapidly. 3. Moreover, steroid hormones and neurotransmitters may operate together to produce effects, and sometimes these effects involve collaborations between groups of neurons. For example, a number of steroid actions in the hippocampus involve the coparticipation of excitatory amino acids. These interactions are evident for the regulation of synaptogenesis by estradiol in the CA1 pyramidal neurons of hippocampus and for the induction of dendritic atrophy of CA3 neurons by repeated stress as well as by glucocorticoid injections. In addition, neurogenesis in the adult and developing dentate gyrus is "contained" by adrenal steroids as well as by excitatory amino acids. In each of these three examples, NMDA receptors are involved. 4. These results not only point to a high degree of interdependency between certain neurotransmitters and the actions of steroid hormones, but also emphasize the degree to which structural plasticity is an important aspect of steroid hormone action in the adult as well as developing nervous system.
Cell Mol Neurobiol 1996 Apr
PMID:Gonadal and adrenal steroids regulate neurochemical and structural plasticity of the hippocampus via cellular mechanisms involving NMDA receptors. 874 63

Granule cells in the adult rat hippocampus do not constitutively express the growth-related axonal protein F1 (a.k.a. B-50, GAP-43, neuromodulin, pp46), yet kainic acid (KA) can induce extensive growth of granule cell axons, the mossy fibers, into the supragranular layer. Does this KA-induced growth occur in the absence of protein F1/GAP-43? Using quantitative in situ hybridization, we found that 16-24 h after KA (10 mg/kg, s.c.) F1/GAP-43 mRNA was in fact induced in granule cells and remained elevated above control levels for at least 20 days. The induction of F1/GAP-43 mRNA in granule cells was blocked either by MK-801 or pentobarbital pretreatment. If pentobarbitol was given 55 min, but not 90 min, after KA, F1/GAP-43 mRNA was also blocked. Since induction of F1/GAP-43 occurred when pentobarbitol was given 90 min after KA, a 35 min window of activation is required, beyond the initial 55 min, for F1/GAP-43 mRNA induction. As both MK-801 and pentobarbital blocked behavioral seizures their anti-convulsant action may be important for blocking F1/GAP-43 mRNA induction. Mossy fiber sprouting observed 30 days after KA was also blocked when either MK-801 or pentobarbital was given prior to KA. These results are consistent with the proposal that protein F1/GAP-43 promotes axonal growth in the adult brain in an input-dependent manner, and may also be of clinical relevance to the molecular mechanisms underlying structural remodeling in epilepsy.
Brain Res Mol Brain Res 1995 Oct
PMID:NMDA receptor blockade prevents kainate induction of protein F1/GAP-43 mRNA in hippocampal granule cells and subsequent mossy fiber sprouting in the rat. 877 42

Understanding and experimentally approaching the processes that underlie the origin and progression of many severe neurological disorders presents a challenge to both clinical and basic researchers. We have found that the origin of some neurological diseases, including a rare form of childhood epilepsy and a neurodegenerative disease associated with peripheral cancers, may be related to production of physiologically active autoantibodies that are directed towards excitatory ionotropic glutamate receptors of the brain. This suggests that some neurological diseases may result from dysfunction of the immune system.
Mol Med Today 1996 Feb
PMID:The role of autoimmunity to glutamate receptors in neurological disease. 879 60

In 1996, we are half-way through the Decade of the Brain, yet we still have few effective treatments for major disorders of the central nervous system. These include affective disorders, epilepsy, neurodegenerative disorders, brain tumours, infections and HIV encephalopathy; sufferers far outnumber the morbidity of cancer or heart disease. Increased understanding of the pharmacology of the brain and its blood supply, and methods for rational drug design, are leading to potential new drug therapies based on highly specific actions on particular target sites, such as neurotransmitter receptors and uptake systems. These methods are capable of reducing the side effects that are common with more general treatments. However, all these treatments and potential treatments meet a formidable obstacle--the blood-brain barrier. In this article, we review the properties of this barrier that complicate drug delivery to the brain, and some of the most hopeful strategies for overcoming or bypassing the barrier in humans.
Mol Med Today 1996 Mar
PMID:Transporting therapeutics across the blood-brain barrier. 879 67

Epilepsy is one of the most common neurological disorders. Both inherited and acquired factors contribute to its multifactorial pathogenesis. A genetic predisposition plays a major role in the aetiology of the common idiopathic generalized epilepsies. Susceptibility genes for two syndromes of idiopathic generalized epilepsies, the benign familial neonatal convulsions and juvenile myoclonic epilepsy, have been assigned to the chromosomal regions 20q13 (EBN1), 8q24 (EBN2) and 6p21 (EJM1). Positional cloning of the mutations causing these traits will help to elucidate the molecular pathways of epileptogenesis and will imply a classification on a neurobiological basis. Insights into the underlying impairment of neuronal excitability should provide new concepts for the development of rational treatment strategies.
Mol Med Today 1996 Apr
PMID:The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology. 879 80

Previous animal research has suggested that the phenytoin arene oxide metabolite is teratogenic in acute studies and that the fetal effects were increased after injecting an inhibitor of microsomal epoxide hydrolase (mEH) (Martz et al., Pharmacol Exp Ther 203:231-239, 1977, Barcellona et al., Teratog Carcinog Mutagen 7:159-168, 1987). We have studied the effects of chronic oral phenytoin exposure in utero and the mEH inhibitor trichloropropene oxide (TCPO) on the prenatal growth and development of an inbred mouse strain with a low incidence of spontaneous oral clefting (C57BL/6J). Chronic daily gastric gavage of phenytoin produced a plasma level (mean 10.7 micrograms/ml on gestation Day 8) within the range recommended to prevent epilepsy in humans; this did not produce an increase in oral clefting or ventricular septal defects in the exposed C57BL/6J pups. It did produce a significant delay in prenatal growth and development, including phalangeal ossification. However, except for percentage resorptions/implantation, there was no synergism between phenytoin and TCPO in contrast to the finding reported by Martz et al. in Swiss mice. This issue was also assessed in a test of the fetal effect of phenytoin injected with TCPO, as had been done by Martz et al. There were no oral clefts or ventricular septal defects or a difference (P > 0.05) in prenatal growth and development in these C57BL/6J pups compared to the chronic gastric phenytoin plus TCPO group. This suggests either that differences in the genotypes of Swiss and C57BL/6J mice may be a contributing factor or that other teratogenic mechanisms were involved.
Biochem Mol Med 1995 Dec
PMID:Phenytoin embryopathy: effect of epoxide hydrolase inhibitor on phenytoin exposure in utero in C57BL/6J mice. 882 76

Glutamate (Glu) uptake is the primary mechanism for its removal from the synapse. In genetic audiogenic seizures (AGS), Glu uptake is elevated prior to the appearance of seizures. Increased Glu uptake is also observed in synaptosomes from normal mice preincubated with lithium or nitroarginine, an NO synthase inhibitor. Pertussis and cholera toxins cause a marked reduction in Glu uptake. In contrast, neither lithium nor nitroarginine affected Glu uptake by synaptosomes from genetic epileptic mice. Arachidonic acid inhibits Glu uptake, whereas synaptosomes from epileptic mouse brain appear to be more sensitive to arachidonic acid as indicated by a shift of the inhibition curve to the left. These observations are indicative of the possible regulation of Glu uptake by second messengers and its alteration in genetic epilepsy.
Mol Chem Neuropathol
PMID:Possible regulation of high-affinity glutamate uptake in synaptosomes of normal and epileptic mice. 887 51

The immediate early gene-encoded enzyme, MAP kinase phosphatase 1 (MKP-1), is thought to be a key element in controlling cellular signalling pathways activated by MAP kinases. Since MAP kinase have been demonstrated to participate in neuronal stimulus-transcription coupling following seizure activity, the present study investigated the induction of MKP-1 in the rat brain after limbic epilepsy. MKP-1 expression was studied with a polyclonal antiserum by Western blots, immunocytochemistry and immuno-electron microscopy at different time periods between 1 and 24 h after kainic acid-induced limbic seizures. MKP-1 induction was identified in dentate granule cells of the hippocampus but not in pyramidal neurons, furthermore in neurons of the outer layers of the neocortex, as well as in neurons of the lateral nucleus of the bed of the stria terminalis. Immuno-electron microscopy demonstrated that MKP-1 was localized in the neuronal nucleus, where the substrate of MKP-1, activated MAP kinases, are also found. In view of the restricted areas of MKP-1 expression and the widespread areas of altered MAP kinases activity it can be concluded that in the majority of CNS populations other mechanisms than MKP-1 induction are responsible for the shut-off of MAP kinases following seizure activity. MKP-1 may contribute in the specific subpopulations where it is induced to the post-translational control of inducible transcription factors of the fos, jun and myc family.
Brain Res Mol Brain Res 1996 Sep 05
PMID:Transient expression of the mitogen-activated protein kinase phosphatase MKP-1 (3CH134/ERP1) in the rat brain after limbic epilepsy. 888 36

Methylguanidine, guanidinoacetic acid and guanidinosuccinic acid are endogenous substances in body tissues. Extremely high levels of these substances are known to be related to the pathogenesis of epilepsy and renal failure such as uremia. In this study it was demonstrated that methylguanidine, guanidinoacetic acid and guanidinosuccinic acid, and arginine generate hydroxyl radicals in aqueous solution. These findings suggest that a high level of guanidino compounds accumulating near or within cells such as neurons (in an epileptogenic focus) or nephrons (in uremic patients) may cause free radical damage leading to these clinical disorders. Arginine may have a similar role in the pathogenesis of hyperarginemia.
Biochem Mol Biol Int 1996 Sep
PMID:Guanidino compounds generate reactive oxygen species. 888 79


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