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J N Simpson

Publications and source records attributed to J N Simpson.

11 recordsLinked to original sources
PubMed1997

Kainic acid-induced sprouting of dynorphin- and enkephalin-containing mossy fibers in the dentate gyrus of the rat hippocampus.

This study utilized Timm histochemistry and immunocytochemistry to determine the prolonged effects of kainic acid on the distribution of dynorphin- and enkephalin-containing mossy fibers in the rat dentate gyrus at progressive time points following kainic acid injection. Beginning 1-2 weeks after kainic acid administration, a progressive increase in the distribution and intensity of staining for supragranular zinc, dynorphin and enkephalin was observed in the dentate gyrus. The kainic acid-induced sprouting of mossy fibers containing dynorphin and enkephalin strongly resembles the pattern observed in the dentate gyrus of humans with temporal lobe epilepsy.

Animals↗
PubMed1995

Forskolin induces preproenkephalin and preprodynorphin mRNA in rat striatum as demonstrated by in situ hybridization histochemistry.

Cyclase response elements (CREs) are located in the promoter regions of several neuropeptide and immediate early genes. Activation of the adenylate cylase/cAMP second messenger cascade leads to phosphorylation of CRE-binding proteins (P-CREBs) which bind to CREs in the promoter regions of these genes and alter their rate of transcription. We have previously reported an increase in striatal immunoreactivity for P-CREB (phosphorylated on Ser-133) and Fos following intracerebroventricular (ICV) injection of H2O-soluble forskolin, a direct activator of adenylate cyclase. Because CREs are located in the promoter regions of the opioid peptide genes, preproenkephalin (PPE) and preprodynorphin (PPD), we investigated what effect continuous ICV infusion of H2O-soluble forskolin has on striatal PPE and PPD mRNA levels. Quantitative in situ hybridization histochemistry demonstrated that continuous activation of the adenylate cyclase/cAMP second messenger cascade results in a significant induction of striatal PPE and PPD mRNA at 6, 24, and 72 h. The sustained induction of striatal PPE and PPD mRNA indicates that pro-opioid gene transcription is not desensitized following 72 h of continuous adenylate cyclase activation. Continuous ICV infusion of 1, 9-dideoxyforskolin, a forskolin analog which does not activate adenylate cyclase, did not induce striatal PPE and PPD mRNA. These data are consistent with cAMP-dependent protein kinase-induced phosphorylation and binding of CREBs to CREs in the promoter regions of pro-opioid genes during sustained activation of adenylate cyclase.

Animals↗
PubMed1995

Repeated amphetamine administration induces a prolonged augmentation of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in rat striatum.

Semi-quantitative immunocytochemistry was used to investigate the levels of cyclase response element-binding protein, phosphorylated cyclase response element-binding protein, Fos and Fos-related antigen immunoreactivity in the striatum of rats after acute or repeated amphetamine administration. Rats were perfused 20 min (phosphorylated cyclase response element-binding protein) or 2 h (cyclase response element-binding protein, phosphorylated cyclase response element-binding protein, Fos, Fos-related antigen) after a single injection (5 mg/kg, i.p.) or five daily injections of amphetamine. The latency to onset of stereotypical behaviors was significantly reduced in rats exposed to repeated amphetamine as compared to acute amphetamine, indicating development of behavioral sensitization. Cyclase response element-binding protein immunoreactivity was not altered in the dorsal or ventral striatum following acute or repeated amphetamine. Phosphorylated cyclase response element-binding protein immunoreactivity was significantly induced 20 min, but not 2 h, following acute amphetamine, whereas a significant induction of phosphorylated cyclase response element-binding protein immunoreactivity was found 20 min and 2 h after repeated amphetamine in the dorsal striatum only. Fos immunoreactivity was significantly induced in the dorsal striatum following acute and repeated amphetamine. Fos immunoreactivity in the core of the nucleus accumbens was significantly increased following repeated amphetamine only. Acute amphetamine induced, and repeated amphetamine further augmented, Fos-related antigen immunoreactivity in the dorsal striatum, while not affecting Fos-related antigen immunoreactivity in the nucleus accumbens. These data demonstrate that repeated amphetamine administration results in a prolonged induction of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in the dorsal striatum, indicating that alterations in striatal gene expression associated with the development of behavioral sensitization may be mediated, in part, by these transcription factors.

Amphetamine↗
PubMed1994

Forskolin increases phosphorylated-CREB and fos immunoreactivity in rat striatum.

Promoter regions of the preproenkephalin, preprodynorphin, and c-fos genes contain cyclase response elements (CREs) as well as AP-1 sites. Activation of the adenylate cyclase cascade leads to phosphorylation of cyclase response element binding proteins (P-CREBs) which then bind CREs in these genes and induce transcription. In this experiment, semi-quantitative immunocytochemistry was used to examine striatal CREB-, P-CREB-, and Fos-like immunoreactivity (IR) 1 h following intracerebroventricular injection of H2O-soluble forskolin. Although forskolin did not alter CREB-IR, forskolin did induce striatal P-CREB-IR and Fos-IR by 2.5- and 10-fold, respectively. These data support a role for P-CREB and/or Fos in regulating opioid peptide gene transcription following direct in vivo activation of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1992

Kainic acid depresses the ex vivo release of dynorphin B and glutamate from rat hippocampal mossy fiber synaptosomes.

This experiment examined the effects of intracerebroventricularly (i.c.v.) administered kainic acid (KA) on the subsequent ex vivo release of L-glutamate (Glu) and dynorphin B-like immunoreactivity (Dyn B-LI) from isolated rat hippocampal mossy fiber (MF) synaptosomes at 4.5 h, 20 h or 48 h after administration of 0.5 microgram/microliter KA. The Dyn B-LI content in the synaptosomal fraction initially decreased at 4.5 h and then rebounded and remained elevated above control levels at 20 h and 48 h. The K(+)-evoked release of Dyn B-LI from the synaptosomes was markedly depressed at 4.5 h after KA and remained significantly below control levels at 20 h and 48 h. In contrast, KA caused no change in the K(+)-evoked release of Glu at 4.5 h as compared to control levels, but did result in a significant decrease in Glu release at 20 h and 48 h. These data indicate a persistent effect of i.c.v. KA on neurotransmission at MF-CA3 synapses in rat hippocampus, resulting in a suppression of the release of Glu as well as the opioid peptide, Dyn B.

Animals↗
PubMed1989

The interaction between kappa-opioid agonist, U-50, 488H, and kainic acid: behavioral and histological assessments.

The effects of a selective kappa-agonist, U-50,488H, on systemic kainic acid-induced behavioral and histological changes were studied in rats. U-50,488H inhibited kainic acid-induced wet dog shakes in a naloxone reversible manner; however, U-50,488H did not protect rats against kainic acid-evoked behavioral seizures. As revealed by histological analysis, kainic acid caused edema and severe neuronal damage in several brain regions, notably in CA1 but also in the CA3 fields of both hippocampi. Pretreatment of rats with U-50,488H markedly protected hippocampal neurons, especially those in CA1, against kainic acid-induced neurotoxicity. Naloxone by itself had little effect on kainic acid-induced seizures or hippocampal neuron loss. Naloxone plus U-50,488H resulted in less severe seizures and, consequently, less hippocampal cell loss than after kainic acid alone. These data indicate that U-50,488H can markedly attenuate the neurotoxic and behavioral consequences of systemic kainic acid administration. However, the mechanism of these effects requires further study with more specific opioid antagonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Effects of D-(-)-aminophosphonovalerate on behavioral and histological changes induced by systemic kainic acid.

In rats, the seizures induced by systemic kainic acid (KA) are followed by extensive neuronal damage, notably in the hippocampal region. We report that the specific N-methyl-D-aspartate (NMDA) receptor antagonist, D-(-)-aminophosphonovalerate (D(-)APV), given i.c.v. prior to or 2 h after i.p. KA injection markedly protected CA1 but not other hippocampal neurons against degeneration. In contrast, D(-)APV had no effect on KA-induced wet dog shakes or on behavioral seizures. We conclude that NMDA receptors participate in the neurotoxic but not in the behavioral effects of systemic KA.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Mu but not delta opioid receptor stimulation intensifies kainic acid-induced neurotoxicity in rat hippocampus.

In the present study, we compared the effects of the selective mu agonist, [D-Ala2-N-methyl-pHe4-Gly-ol]-enkephalon (DAGO), and the selective delta agonist, [D-Pen2,5]-enkephalin (DPDPE), on kainic acid-induced neurotoxicity in rats. Infusion of kainic acid (0.5 ug/1.5 ul, ic.v.) alone caused pyramidal cell loss predominantly in hippocampal field CA3 with minimal involvement of the CA1 field. Coadministration of DAGO plus kainic acid into the lateral ventricle intensified the extent of degeneration of hippocampal pyramidal cells in the CA1 field. The potentiating effect of DAGO was completely blocked by naltrexone. In contrast, DPDPE had no significant effect on kainic acid-induced neurotoxicity. Thus, activation of mu but not delta receptors intensifies the neurotoxic effects of kainic acid in the hippocampus.

Analgesics↗
PubMedDate not supplied

Protein tyrosine kinase inhibitors decrease lipopolysaccharide-induced proinflammatory cytokine production in mixed glia, microglia-enriched or astrocyte-enriched cultures.

Proinflammatory cytokines, tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), produced by glial cells have been implicated in the neuropathogenesis of various diseases. However, the signal transduction pathway(s) for the production of these cytokines in glial cells are not well understood. This study examined the effects of two potent protein tyrosine kinase inhibitors, genistein and tyrphostin A25, on lipopolysaccharide (LPS)-induced production of TNF alpha, IL-1 alpha, and IL-6 in mouse primary mixed glia, microglia- or astrocyte-enriched cultures. LPS dose-dependently increased the production of TNF alpha, IL-1 alpha, and IL-6 from the mixed glia cultures. Genistein or tyrphostin A25 significantly inhibited the LPS-induced production of these cytokines. The LPS-induced TNF alpha, IL-1 alpha, and IL-6 production in microglia- or astrocyte-enriched cultures were also inhibited by tyrphostin A25. These results demonstrate that protein tyrosine kinases are involved in the signaling events of the LPS-induced production of TNF alpha, IL-1 alpha, or IL-6 in microglia or astrocytes, which may provide insights into therapeutic interventions in the pathway for cytokine production in the brain.

Animals↗