Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat.

Cerebral ischemia followed by oxygen reperfusion induced apoptosis in hippocampal neurons in the stroke-prone spontaneously hypertensive rat (SHRSP) but not in Wistar Kyoto rats (WKY). We investigated whether 2-phenyl-1,2-benzisoselenazol-3(2H)-one, also called PZ51 (ebselen), useful for treating ischemic damage or antihypertension in the brain, can protect against ischemic neuronal damage in SHRSP. In this study, we compared the effects of ebselen, carvedilol, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) as well as vitamin E, added to cultures of neurons after reoxygenation (20% O(2)) following hypoxia (1% O(2)). SHRSP neurons died rapidly during reoxygenation following hypoxia but were rescued in large measure by 10 muM ebselen (neuronal death; 2.7+/-1.4%). In order of neuroprotective potency, the agents ranked as follows: ebselen>carvedilol>MCI-186>vitamin E. In vivo, strong neuroprotection by ebselen was observed in the hippocampal CA1 region of SHRSP (32.9+/-9.5 apoptotic neuron/1000 neurons, 30 mg/kg/day). Ebselen prevented apoptosis as confirmed by morphological observations in vivo. Its effect was associated with the expression of Bcl-2 and Bax. These findings suggest that ebselen has a marked inhibitory effect on neuronal damage during stroke. Ebselen may be effective in the prevention and/or treatment of neurodegenerative diseases associated with excessive apoptosis in patients with stroke.

Anticancer effects of preoperative chemotherapy on colorectal carcinoma.

This study was designed to evaluate the efficacy of preoperative chemotherapy and to investigate the relationship between the histopathologic response and prognosis in patients with colorectal carcinoma. Thirty-six previously untreated patients with advanced colorectal carcinoma were consecutively enrolled in this study and received preoperative N-(2-tetrahydrofuryl-5-fluorouracil (FT-207) by suppository. The histopathologic response was investigated. Histopathologically, 14 patients had no response, 19 responded slightly, 2 moderately and 1 had a complete response to the chemotherapy. The extent of the histopathologic response to chemotherapy was greater in the deeper layers of the invaded tissue. There was no relation between the location of the tumor and the extent of the histopathologic response. Based on clinical cancer staging, the overall 5-year survival rate was 100% in patients with Duke's A and Duke's B cancer and 45% in patients with Duke's C cancer; the 3-year survival rate was 25% in patients with Duke's D cancer. The 5-year survival rate for those with a positive histopathologic response to chemotherapy was 71%, whereas that for the nonresponders was 79%. Mild chemotherapy in the form of FT-207 suppositories was found to be effective histopathologically. However, no relationship was seen between the histopathologic response and survival rate.

Two novel testicular serine proteases, TESP1 and TESP2, are present in the mouse sperm acrosome.

To identify a novel candidate(s) for acrosomal proteins that act on the sperm/egg interaction, a DNA fragment was PCR-amplified from a cDNA library of acrosin-deficient mouse testis and then used as a probe to screen a mouse testis cDNA library. Complementary DNA clones encoding each of two similar but different serine proteases, TESP1 and TESP2, have been identified. The nucleotide sequences of these clones indicate that mouse TESP1 and TESP2 are initially synthesized as preproproteins of 367 and 366 amino acids, respectively. Comparison of the two TESP sequences with those of typical serine proteases suggests that each TESP zymogen is probably converted into a two-chain mature enzyme consisting of light and heavy chains covalently linked by a single pre-existing disulfide bond. The conversion may be accomplished by another protease(s) with a trypsin-like cleavage specificity, since it is unlikely that the mature TESP1 and TESP2 are capable of splitting the Lys-Ile bond between the light and heavy chains. Northern blot analysis of total cellular RNA demonstrates that the TESP1 and TESP2 genes are expressed only in the testis, and the transcripts are abundantly present in the haploid round spermatids. Moreover, immunocytochemical analysis of mouse cauda epididymal sperm using affinity-purified antibodies reveals that these two TESPs are both localized in the sperm acrosome and are released during the acrosome reaction induced by calcium ionophore A23187. These findings provide additional clues for elucidating the mechanisms involved in the sperm/egg interactions, including penetration of the zona pellucida by sperm.