Characterization of primary structure and tissue expression profile of the chicken apical sodium-dependent bile acid transporter mRNA.

The ileal apical sodium-dependent bile acid cotransporter (ASBT) plays an essential role in the absorption of bile acids from intestinal lumina. ASBT cDNA has been cloned from mammalian and fish species, and the primary structure of the protein and expression properties of the mRNA have been characterized. In this study, we identified chicken ASBT mRNA by cDNA cloning. Chicken ASBT cDNA consisted of 91 bp of the 5'-untranslated region, 1,083 bp of the coding region, and 1,896 bp of the 3'-untranslated region. The cDNA encoded a protein of 360 amino acids showing significant sequence identity with mammalian and fish ASBT. The amino acid residues known to participate in the functions of mammalian ASBT were conserved in chicken ASBT. Real-time polymerase chain reaction analysis revealed that chicken ASBT mRNA was expressed at markedly higher levels in the ileum and proximal colon/rectum, relatively lower levels in the kidney, and very low levels in the jejunum and cecum. Expression levels in the ileum markedly increased after hatching, reached the highest levels on day 7 posthatching, and then decreased to adult levels. A similar expression pattern was observed in the proximal colon/rectum except for the significant decrease from day 7 posthatching to day 21 posthatching. These results suggest that chicken ASBT functions as a bile acid transporter in the ileum and proximal colon/rectum, particularly during the early posthatching period.

Changes in expression levels of neurotensin precursor and receptor mRNA in chicken intestinal tissues and liver during late embryonic and early posthatching development.

Neurotensin is a tridecapeptide that has multiple functions as a neurotransmitter and as a circulating hormone. Neurotensin and its related peptide, LANT6, have been isolated in the chicken, but the mRNA encoding these peptides has not been identified. In this study, we first cloned the cDNA for the chicken neurotensin precursor mRNA from the duodenum and characterized its primary structure and then investigated tissue expression patterns of neurotensin precursor and receptor mRNA. The cDNA encoded a protein of 495 amino acids that contains the sequences of chicken neurotensin and LANT6 in the C-terminal region. Real-time PCR analysis showed that the neurotensin precursor mRNA is preferentially expressed in intestinal tissues, such as the duodenum, jejunum, ileum, and colon/rectum, with temporal increases during the hatching period. The expression levels of neurotensin receptor 1 mRNA were relatively higher during the late embryonic period compared with the posthatching period in the duodenum and jejunum, whereas the expression levels were higher in the colon/rectum during the posthatching period. In the liver, the expression levels of neurotensin receptor 1 were markedly increased during the early posthatching period. These results suggest that chicken neurotensin is involved in the regulation of gastrointestinal and hepatic functions, especially during the hatching period.

Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease.

A high survival rate of grafted dopamine neurons is crucial for reversing neurological deficits following brain tissue transplantation in Parkinson's disease. For unknown reasons the survival rate of transplanted dopamine neurons is only around 10% in experimental animals. The hypothesis that oxidative stress causes the loss of transplanted neurons was tested by grafting neurons from transgenic mice that overexpress Cu/Zn superoxide dismutase. Compared with the survival of those taken from non-transgenic littermates, the survival was 4 times higher for the transgenic dopamine neurons with a concomitant more extensive functional recovery. The results provide direct support for the free radical hypothesis of dopaminergic neuron death in brain tissue grafting.

Low-calcium dialysate improves mineral metabolism in hemodialysis patients.

BACKGROUND: The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommend 1.25 mmol/l Ca dialysate for both hemodialysis and peritoneal dialysis, while 1.5 mmol/l Ca dialysate has been used in our dialysis center. METHODS: Therefore, we switched the dialysate calcium concentration from 1.5 - 1.25 mmol/l and observed the effects on serum calcium (S-Ca), phosphorus (S-P), 1-84 parathyroid hormone (whole PTH, w-PTH), bone-specific alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) for 6 months in 58 hemodialysis patients. Prescription of active vitamin D (VD) metabolites and Ca carbonate was increased in response to the changes in laboratory data. RESULTS: Decrease of S-Ca was evident at 2 weeks and S-Ca remained low for 6 months. Transient elevation of S-P, which might be caused by stimulated bone resorption, was observed after the switch. In patients with low PTH (w-PTH less than 90 pg/ml before the switch), continuous increase of w-PTH, BAP, and TRACP-5b was observed. This appeared to be a favorable response because the risk ofadynamic bone disease was high in this group of patients. On the other hand, acute elevation of the 3 parameters was well-controlled in patients with moderate and high PTH (w-PTH from 90 - 180 pg/ml, w-PTH more than 180 pg/ml, respectively) by increased dosage of active VD. CONCLUSION: These results demonstrate that 1.25 mmol/l Ca dialysate improved mineral metabolism by lowering S-Ca and releasing oversuppression of PTH. Our data also suggest that appropriate use of active VD could prevent acute rise of PTH.

Development of a quasi-monoenergetic neutron field using the 7Li(p,n)7Be reaction in the energy range from 250 to 390 MeV at RCNP.

A quasi-monoenergetic neutron field using the (7)Li(p,n)(7)Be reaction has been developed at the ring cyclotron facility at the Research Center for Nuclear Physics (RCNP), Osaka University. Neutrons were generated from a 10-mm-thick Li target injected by 250, 350 and 392 MeV protons and neutrons produced at 0 degrees were extracted into the time-of-flight (TOF) room of 100-m length through the concrete collimator of 10 x 12 cm aperture and 150 cm thickness. The neutron energy spectra were measured by a 12.7-cm diam x 12.7-cm long NE213 organic liquid scintillator using the TOF method. The peak neutron fluence was 1.94 x 10(10), 1.07 x 10(10) and 1.50 x 10(10) n sr(-1) per muC of 250, 350 and 392 MeV protons, respectively. The neutron spectra generated from various thick (stopping length) targets of carbon, aluminium, iron and lead, bombarded by 250 and 350 MeV protons, were also measured with the TOF method. Although these measurements were performed to obtain thick target neutron yields, they are also used as a continuous energy neutron field. These neutron fields are very useful for characterising neutron detectors, measuring neutron cross sections, testing irradiation effects for various materials and performing neutron shielding experiments.

Fetal tissue transplants in animal models of Huntington's disease: the effects on damaged neuronal circuitry and behavioral deficits.

Accumulating evidence indicates that grafts of embryonic neurons achieve the anatomical and functional reconstruction of damaged neuronal circuitry. The restorative capacity of grafted embryonic neural tissue is most illustrated by studies with striatal tissue transplantation in animals with striatal lesions. Striatal neurons implanted into the lesioned striatum receive some of the major striatal afferents such as the nigrostriatal dopaminergic inputs and the gluatmatergic afferents from the neocortex and thalamus. The grafted neurons also send efferents to the primary striatal targets, including the globus pallidus (GP, the rodent homologue of the external segment of the globus pallidus) and the entopeduncular nucleus (EP, the rodent homologue of the internal segment of the globus pallidus). These anatomical connections provide the reversal of the lesion-induced alterations in neuronal activities of primary and secondary striatal targets. Furthermore, intrastriatal striatal grafts improve motor and cognitive deficits seen in animals with striatal lesions. Since the grafts affect motor and cognitive behaviors that are critically dependent on the integrity of neuronal circuits of the basal ganglia, the graft-mediated recovery in these behavioral deficits is most likely attributable to the functional reconstruction of the damaged neuronal circuits. The fact that the extent of the behavioral recovery is positively correlated to the amount of grafted neurons surviving in the striatum encourages this view. Based on the animal studies, embryonic striatal tissue grafting could be a viable strategy to alleviate motor and cognitive disorders seen in patients with Huntington's disease where massive degeneration of striatal neurons occurs.

[New CT program simulating kidney displacement during retroperitoneal laparoscopic nephrectomy].

A total of 12 patients with malignant localized renal or ureteral neoplasms underwent multi-slice computed tomography. Imaging data were sent to the dedicated workstation to create volume rendering and virtual laparoscopic images of the kidney which was displaced ventrally with retroperitoneal balloon. These findings were compared with video images obtained during retroperitoneal laparoscopic nephrectomy. The kidney displacement simulator depicted all renal arteries (100% sensitivity) and 13 of 14 renal veins (93% sensitivity). Hilar anatomy, including the tumor, major vessels and their relationships were visualized as in the actual laparoscopic views. The desired portions of major vessels as well as the left adrenal and gonadal veins visualized with this system completely corresponded with the actual laparoscopic images during surgery. The kidney displacement simulator is useful to foresee desired portions of major vessels and branched small vessels such as the adrenal or gonadal veins in advance of surgery. It is thus able to guide surgeons and reduce operative risks and possible complications.

Characterization of primary structure and post-hatching increase in chicken cytosolic acetoacetyl-coA thiolase in the liver.

Acetoacetyl-CoA thiolase (EC 2.3.1.9) catalyzes the cleavage of acetoacetyl-CoA into acetyl-CoA and its reverse reaction, the synthesis of acetoacetyl-CoA. Cytosolic acetoacetyl-CoA thiolase ( CT: ) is a key enzyme in the initial step of the cholesterol synthesis pathway. In the present study, we characterized the amino acid sequence of chicken CT and the tissue distribution of its mRNA and protein, together with their developmental changes in the liver. The amino acid sequence encoded by the nucleotide sequence of chicken CT cDNA showed a higher overall identity with those of human (74.3%) and rat (74.6%) CTs. Amino acid residues known to participate in enzymatic activity in human CT are conserved in chicken CT. Real-time PCR analysis revealed the expression of CT mRNA in the liver, kidney, adrenal gland, jejunum and ovary of adult hens, with higher levels in the liver, kidney, adrenal gland and ovary. Western blot analysis detected an immunoreactive protein of 41 kDa from cytoplasmic fraction but not particulate fractions of adult chicken liver. The immunoreactive protein was detected in all the tissues. The mRNA levels in the liver rapidly increased after hatching, with a maximum on d 5 post-hatching, after which they gradually decreased to adult levels. A similar change was observed in the protein levels. The increase in transcription and protein synthesis of CT suggests that the synthetic pathway of cholesterol from acetyl-CoA produced by CT replaces the hydrolysis of accumulated cholesteryl ester in the liver, in response to a change in the nutrient source from the lipid-rich yolk to a lower-lipid diet during the early post-hatching period.

Generation of dopaminergic neurons in the adult brain from mesencephalic precursor cells labeled with a nestin-GFP transgene.

Mesencephalic precursor cells may one day provide dopaminergic neurons for the treatment of Parkinson's disease. However, the generation of dopaminergic neurons from mesencephalic precursors has been difficult to follow, partly because an appropriate means for recognizing mesencephalic ventricular zone precursors has not been available. To visualize and isolate mesencephalic precursor cells from a mixed population, we used transgenic mice and rats carrying green fluorescent protein (GFP) cDNA under the control of the nestin enhancer. nestin-driven GFP was detected in the mesencephalic ventricular zone, and it colocalized with specific markers for neural precursor cells. In addition, data from flow-cytometry indicated that Prominin/CD133, a cell-surface marker for ventricular zone cells, was expressed specifically in these GFP-positive (GFP(+)) cells. After sorting by fluorescence-activated cell sorting, the GFP(+) cells proliferated in vitro and expressed precursor cell markers but not neuronal markers. Using clonogenic sphere formation assays, we showed that this sorted population was enriched in multipotent precursor cells that could differentiate into both neurons and glia. Importantly, many neurons generated from nestin-GFP-sorted mesencephalic precursors developed a dopaminergic phenotype in vitro. Finally, nestin-GFP(+) cells were transplanted into the striatum of a rat model of Parkinson's disease. Bromodeoxyuridine-tyrosine hydroxylase double-labeling revealed that the transplanted cells generated new dopaminergic neurons within the host striatum. The implanted cells were able to restore dopaminergic function in the host striatum, as assessed by a behavioral measure: recovery from amphetamine-induced rotation. Together, these findings indicate that precursor cells harvested from the embryonic ventral mesencephalon can generate dopaminergic neurons able to restore function to the chemically denervated adult striatum.

Testis-specific and developmentally induced expression of a ghrelin gene-derived transcript that encodes a novel polypeptide in the mouse.

Ghrelin is a novel growth hormone-releasing peptide isolated from rat stomach. In the present study, we report expression of a ghrelin gene-derived transcript (GGDT) in the mouse testis. Analysis of GGDT cDNA revealed that the 68 bp sequence at the 5'-end was unique and the remaining 252 bp sequence was identical with the sequence encoded by exons 4 and 5 of mouse ghrelin gene. The 5'-unique sequence encoded 12 amino acid residues being in-frame with the C-terminal 42 amino acid sequence of mouse ghrelin. The 54-amino-acid polypeptide encoded by GGDT contained no apparent signal peptide sequence but possessed a nuclear localization signal-like sequence. Ghrelin mRNA was extensively expressed in the stomach, while GGDT was expressed only in the testis. The 5'-unique sequence of GGDT was identified between exons 3 and 4 of the ghrelin gene, indicating that GGDT was generated by alternative usage of the 68 bp exon as the testis-specific first exon. The GGDT expression in the testis was initiated and increased after 2 weeks of postnatal period. These results indicate that the expression of GGDT is regulated in testis-specific and developmental stage-specific manners.

Two novel first exons in the prolactin receptor gene are transcribed in a tissue-specific and sexual maturation-dependent manner to encode multiple 5'-truncated transcripts in the testis of the chicken.

Cloning and sequencing of the chicken prolactin receptor (PRLR) gene segment from the transmembrane domain to the box 2 motif revealed the presence of the two testis-specific first exons, TSE-1 and TSE-2, encoding the unique 5'-end sequences of the reported and newly identified multiple 5'-truncated PRLR transcripts containing only the cytoplasmic domain in the testis. TSE-1 was located downstream of the exon encoding the transmembrane domain and TSE-2 presented downstream of the exon encoding the box 1 motif. These findings indicate that the box 1-containing 5'-truncated transcripts are generated by the utilization of TSE-1 as the first exon with distinct splicing donor sites to the box 1-containing exon, and that the utilization of TSE-2 as the first exon and its splicing to the box 2-containing exon results in the generation of the box 1-lacking transcript. Three transcription initiation sites for the box 1-containing 5'-truncated transcripts and two transcription initiation sites for the box 1-lacking transcript were detected by the RNase protection assays. Reverse transcription-polymerase chain reaction analysis showed that the expression levels of all these 5'-truncated PRLR transcripts are simultaneously increased during sexual maturation, accompanying the decrease of the amount of the canonical full-length transcript for PRLR.

Study of the neutron beam line shield design for JSNS.

The JSNS, a spallation neutron source of J-PARC (JAERI-KEK Joint Project of the High Intensity Proton Accelerator) has 23 neutron beam lines. In the present study, a database was formulated for an optimum shielding design using the MCNP-X code. The calculations involved two steps. In the first step, the neutron distributions were created in the typical neutron beam line with a model that included the spallation neutron source target. The neutron currents evaluated flowed from the duct into the duct wall which was the boundary source for the bulk shield surrounding the beam line. In the second step, bulk-shield calculations were performed for the various shielding materials (iron, concrete, heavy concrete and so on) used and their composites up to thicknesses of 3 m. The results were compared with each other. Composite material shields of iron and such hydrogeneous materials as polyethylene or concrete were more effective. A typical design was prepared for a beam line within 25 m distance from a moderator, as a sample.

Radiation streaming experiment through a labyrinth of the 12 GeV proton accelerator facility at KEK(2)--TLD REM-counter method.

The doses of radiation streaming through a labyrinth were measured using thermoluminescence dosemeters (TLDs) and neutron moderators for TLDs at the neutrino beam line of the 12 GeV proton accelerator facility of High Energy Accelerator Research Organization (KEK). The calculated doses using the Monte Carlo code, MCNPX basically agreed with the experimental results. However, unexpectedly, the calculated neutron doses were smaller than the measured ones along the upstream side of the labyrinth.

Radiation safety design for the J-PARC Project.

The High-Intensity Proton Accelerator Project, named J-PARC, is in progress, with the aim of enabling studies on the latest basic science and the advancement of nuclear technology. In the project, a high-energy proton accelerator complex with the world's highest instantaneous intensity is under construction. In order to establish a reasonable shielding design, both simplified and detailed design methods were used in the shielding design of J-PARC. This paper reviews the present status of the radiation safety design study for J-PARC.

Arrangement of high-energy neutron irradiation field and shielding experiment using 4 m concrete at KENS.

An irradiation field of high-energy neutrons produced in the forward direction from a thick tungsten target bombarded by 500 MeV protons was arranged at the KENS spallation neutron source facility. In this facility, shielding experiment was performed with an ordinary concrete shield of 4 m thickness assembled in the irradiation room, 2.5 m downstream from the target centre. Activation detectors of bismuth, aluminium, indium and gold were inserted into eight slots inside the shield and attenuations of neutron reaction rates were obtained by measurements of gamma-rays from the activation detectors. A MARS14 Monte Carlo simulation was also performed down to thermal energy, and comparisons between the calculations and measurements show agreements within a factor of 3. This neutron field is useful for studies of shielding, activation and radiation damage of materials for high-energy neutrons, and experimental data are useful to check the accuracies of the transmission and activation calculation codes.

Organization of the mouse ghrelin gene and promoter: occurrence of a short noncoding first exon.

Ghrelin is a growth hormone-releasing peptide recently discovered in the stomach of rat and human as an endogenous ligand for growth hormone-secretagogue receptor. In the present study, a full-length cDNA for mouse ghrelin has been cloned from the stomach using the oligo-capping and rapid amplification methods, and the organization of its gene and promoter has been analyzed. The mouse ghrelin cDNA was 521 bp long, consisting of 44 bp 5'-noncoding region, 354 bp coding region encoding a pre-proghrelin composed of 117 amino acid residues and 123 bp 3'-noncoding region. The genomic sequence analysis has revealed that the mouse ghrelin gene consists of 5 exons and 4 introns. The first exon was revealed to be only 19 bp long presented at the noncoding region of cDNA. The identical 19 bp sequence was also found as the first exon at the 5'-end of full-length rat ghrelin cDNA obtained from the stomach. A TATA box-like sequence, TATATAA was localized 24 bp upstream of the transcription start site of the mouse ghrelin gene. The sequence of the 5'-promoter region of mouse ghrelin gene including the TATA-like sequence and short exon 1 was highly homologous to that of reported human ghrelin gene. These findings suggest that the structure of the promoter region including the short noncoding first exon and its transcriptional regulation are conserved among the mammalian ghrelin genes.

Prostaglandin E receptor subtypes in mouse osteoblastic cell line.

PGE2 is one of the key molecules in the osteoblast. It is the major prostanoid in the bone, and its production is under the control of both systemic and local factors. PGE2 has been reported to have multiple actions in the osteoblast, such as growth promotion and cell differentiation. To better understand the action of PGE2 in the osteoblast, we determined the PGE receptor subtypes in MC3T3-E1, an osteoblastic cell line derived from the normal mouse calvaria. Northern blot analysis revealed that EP1 and EP4 subtypes are expressed in MC3T3-E1. In contrast, EP3 subtype was not detected by either Northern blot analysis or RT-PCR. The contribution of each subtype was evaluated by studying the effects of subtype-specific analogs on osteoblastic function at confluency and 5 days after confluency. An EP1 agonist, 17-phenyl-omega-trinor PGE2, increased DNA synthesis and decreased alkaline phosphatase activity. 11-Deoxy-PGE1, and EP2 and EP4 agonist, decreased DNA synthesis and increased alkaline phosphatase activity at both stages. Butaprost, an EP2-selective agonist, showed effects similar to those of 11-deoxy-PGE1 only at confluency. Another and more differentiated osteoblastic marker, osteocalcin production, was detectable and was stimulated by 11-deoxy-PGE1 only 5 days after confluency. The exposure of these cells to EP1 agonist changed the cell shape to a more fibroblastic appearance. These results indicate that EP1, EP4, and probably EP2 are present in MC3T3-E1 cells; EP1 promotes cell growth, and EP2 and EP4 mediate differentiation of the osteoblast. Furthermore, the decreased response to EP2-specific agonist 5 days after confluency suggests that the expression of PGE receptor subtype is dependent on the stage of osteoblastic differentiation. This is the first report to determine PGE receptor subtypes in the bone.

Intrahepatic metastases in hepatocellular carcinoma: the role of the portal vein as an efferent vessel.

The mechanism and pathogenesis of the high frequency of intrahepatic metastasis in hepatocellular carcinoma (HCC) has not yet been elucidated. Two hundred and thirty one tumors (< or = 5 cm in diameter) of resected specimens of HCC were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens selected at random from the 231 tumors. The most frequent site for tumor spread in HCC was capsular invasion followed by extracapsular invasion, vascular invasion, and finally intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and the frequency of vascular invasion (correlation coefficient = 0.998). Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in six tumors. In all eight patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that tumor spread in HCC progresses from capsular invasion to intrahepatic invasion and that the portal vein may act as an efferent tumor vessel.

Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols.

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.

An increase in intracellular levels of cyclic AMP produces trophic effects on striatal neurons developing in culture.

Cyclic AMP-dependent kinases have been suggested to constitute signal transduction pathways involved in the regulation of neuronal development and survival. The present study examined whether elevated levels of cyclic AMP exhibit trophic activities on rat striatal neurons grown under serum-free culture conditions. Treatment with dibutyryl cyclic AMP, a permeable cyclic AMP, increased GABA uptake and immunocytochemically detectable levels of proteins such as c-Fos and calbindin-D28k. Neuronal survival was promoted by dibutyryl cyclic AMP only in lower density cultures. Chronic exposure of neurons to dibutyryl cyclic AMP enhanced the morphological development of calbindin-D28k-positive neurons. Furthermore, pretreatment with dibutyryl cyclic AMP afforded neuroprotection against N-methyl-D-aspartate-induced excitotoxicity. The dibutyryl cyclic AMP-induced trophic effects above were blocked by adenosine 3',5'-cyclic monophosphothioate, a specific inhibitor of cyclic AMP-dependent kinases. We also examined whether cyclic AMP is involved in trophic effects provided by membrane depolarization induced by high K+ and growth factors such as basic fibroblast growth factor and insulin-like growth factor-1. Depolarization, but not the growth factors, increased intracellular levels of cyclic AMP. Adenosine 3',5'-cyclic monophosphothioate diminished depolarization increases in GABA uptake, whereas it did not affect the trophic effect of the growth factors. Co-treatment with the growth factors and dibutyryl cyclic AMP produced additive effects on both increases in GABA uptake and neuroprotection against excitotoxicity. The present results indicate that cyclic AMP-dependent kinases play roles in mediating differentiation and survival of developing striatal neurons. Signalling pathways activated by either basic fibroblast growth factor or insulin-like growth factor-1 are independent of those involving cyclic AMP. In contrast, depolarization-induced trophic effects are mediated, at least in part, by cyclic AMP-dependent pathways. Protective actions of dibutyryl cyclic AMP against excitotoxic injury as well as the additive effects with the growth factors are of potential interest in the experimental therapy of acute or chronic neurodegenerative diseases.