Tryptophan-derived indole compounds have been widely investigated as antioxidants and as free-radical scavengers. Indole-3-propionic acid (IPA), one of these compounds, is a deamination product of tryptophan. In the present study, we used Mongolian gerbils to investigate IPA's neuroprotective effects against ischemic damage and its antioxidative effects in the hippocampal CA1 region (CA1) after 5 min of transient forebrain ischemia. The repeated oral administration of IPA (10 mg/kg) for 15 days before ischemic surgery protected neurons from ischemic damage. In this group, the percentage of cresyl violet-positive neurons in the CA1 was 56.8% compared with that in the sham group. In the vehicle-treated group, glial fibrillary acidic protein (GFAP)-, S-100-, and vimentin-immunoreactive astrocytes and ionized calcium-binding adapter molecule 1 (Iba-1)- and isolectin B4 (IB4)-immunoreactive microglia were activated 4 days after ischemia/reperfusion, whereas in the IPA-treated ischemic group, GFAP, S-100, Iba-1, and IB4, but not vimentin, immunoreactivity was distinctly lower than that in the vehicle-treated ischemic groups. The administration of IPA significantly decreased the level of 4-hydroxy-2-nonenal, a marker of lipid peroxidation, in ischemic hippocampal homogenates compared with that in the vehicle-treated ischemic groups at various times after ischemia/reperfusion. In addition, immunostaining for 8-hydroxy-2'-deoxyguanosine showed DNA damage in pyramidal neurons in the ischemic CA1 was significantly lower in the IPA-treated ischemic groups than in the vehicle-treated ischemic groups. These results suggest that IPA protects neurons from ischemia-induced neuronal damage by reducing DNA damage and lipid peroxidation.

Tanshinone I (TsI) is an important lipophilic diterpene extracted from Danshen (Radix Salvia miltiorrhizae) and has been used in Asia for the treatment of cerebrovascular diseases such as ischemic stroke. In this study, we examined the neuroprotective effect of TsI against ischemic damage and its neuroprotective mechanism in the gerbil hippocampal CA1 region (CA1) induced by 5 min of transient global cerebral ischemia. Pre-treatment with TsI protected pyramidal neurons from ischemic damage in the stratum pyramidale (SP) of the CA1 after ischemia-reperfusion. The pre-treatment with TsI increased the immunoreactivities and protein levels of anti-inflammatory cytokines [interleukin (IL)-4 and IL-13] in the TsI-treated-sham-operated-groups compared with those in the vehicle-treated-sham-operated-groups; however, the treatment did not increase the immunoreactivities and protein levels of pro-inflammatory cytokines (IL-2 and tumor necrosis factor-α). On the other hand, in the TsI-treated-ischemia-operated-groups, the immunoreactivities and protein levels of all the cytokines were maintained in the SP of the CA1 after transient cerebral ischemia. In addition, we examined that IL-4 injection into the lateral ventricle did not protect pyramidal neurons from ischemic damage. In conclusion, these findings indicate that the pre-treatment with TsI can protect against ischemia-induced neuronal death in the CA1 via the increase or maintenance of endogenous inflammatory cytokines, and exogenous IL-4 does not protect against ischemic damage.

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Abstract. Vascular smooth muscle contraction is mediated by activation of extracellular signalregulated kinase (ERK) 1 / 2, an isoform of mitogen-activated protein kinase (MAPK). However, the role of stress-activated protein kinase /c-Jun N-terminal kinase (JNK) in vascular smooth muscle contraction has not been defined. We investigated the role of JNK in the contractile response to norepinephrine (NE) in rat aortic smooth muscle. NE evoked contraction in a dosedependent manner, and this effect was inhibited by the JNK inhibitor SP600125. NE increased the phosphorylation of JNK, which was greater in aortic smooth muscle from hypertensive rats than from normotensive rats. NE-induced JNK phosphorylation was significantly inhibited by SP600125 and the conventional-type PKC (cPKC) inhibitor Gö6976, but not by the Rho kinase inhibitor Y27632 or the phosphatidylinositol 3-kinase inhibitor LY294002. Thymeleatoxin, a selective activator of cPKC, increased JNK phosphorylation, which was inhibited by Gö6976. SP600125 attenuated the phosphorylation of caldesmon, an actin-binding protein whose phosphorylation is increased by NE. These results show that JNK contributes to NE-mediated contraction through phosphorylation of caldesmon in rat aortic smooth muscle, and that this effect is regulated by the PKC pathway, especially cPKC.

Effects of intrapancreatic cholinergic activation by electrical field stimulation (EFS) on secretin-stimulated pancreatic exocrine secretion were investigated in the totally isolated perfused rat pancreas. EFS at 15 V, 2 ms, and 8 Hz for 45 min markedly increased spontaneous pancreatic secretion. This increase was completely inhibited by tetrodotoxin (1 μM) but not by hexamethonium (100 μM). Atropine (2 μM) significantly reduced the EFS-evoked volume flow and amylase output by 52% and 80%, respectively. EFS further increased the secretin (12 pM)-stimulated pancreatic secretion of fluid and amylase. The increases of the two parameters were significantly suppressed by atropine by 28% and 72%, respectively. Interestingly, EFS significantly increased concentrations of somatostatin-like immunoreactivity in portal venous effluents. When pertussis toxin (200 ng/ml) or rabbit antisomatostatin serum (0.1 ml/10 ml; titer of 1:50,000) was intra-arterially administered, EFS further increased the secretin-stimulated pancreatic secretion. In conclusion, the activation of intrapancreatic cholinergic neurons potentiated the secretin action on pancreatic exocrine secretion in the rat. This potentiating effect was significantly reduced by local somatostatin released during EFS that activated intrapancreatic cholinergic tone.

Expression and age-related changes of calbindin-D28k (CB), parvalbumin (PV), and calretinin (CR) in the main olfactory bulb of the dog were investigated by immunohistochemistry and western blot analysis. Neurons that expressed these calcium-binding proteins showed a characteristic laminar distribution. Most of CB-immunoreactive neurons were observed in the glomerular layer (GL) and the inner sublayer of the external plexiform layer (EPL). Most of PV-immunoreactive neurons were observed in the outer sublayer of the EPL. CR-immunoreactive neurons were mainly distributed in the GL and the granule cell layer. With regard to age-related changes, CB-immunoreactive neurons in the GL were stable among all age groups; however, in the EPL they decreased with age. PV-immunoreactive neurons decreased in middle-aged and aged groups. However, CR-immunoreactive neurons were not decreased in middle-aged and aged groups. These results suggest that CB-immunoreactive neurons in the EPL were most sensitive to aging, and that their reduction may be related to aging in the dog.