Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex.

Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy.

Anti-arthritic and immunoregulatory effects of TI-31 on collagen-induced arthritis.

TI-31 (TEI-3096, 6-p-chlorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyr imidine) reduced bovine type II collagen-induced arthritis (CIA) in rats in a time- and dose-dependent manner. Oral TI-31 treatment in doses of 10 and 50 mg/kg daily for 7 days prior to collagen immunization depressed the development of arthritis. However, it had no obvious effect on CIA when administered daily for a 7-day or 28-day period after the immunization. This compound was also ineffective against the established arthritis. On the contrary, cyclophosphamide, dexamethasone, or ibuprofen strongly protected the animals from the development of arthritis and/or cured the established arthritis by these dose regimens. Both humoral and delayed-type hypersensitivity skin responses to bovine type II collagen were decreased in rats treated with TI-31 daily for 7 days before the induction of arthritis. These results suggest that TI-31 depresses CIA by regulating the immune response to collagen through a mechanism different from that of anti-inflammatory drugs or immunosuppressants.

Inhibitory effect of TI-31 on autoimmune nephritis in NZB/NZW F1 mice through regulation of the immune response.

TI-31 (TEI-3096; 6-p-chlorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyr imidine) is a novel immunomodulator. Various nephritic changes observed in female NZB/NZW F1 (B/W) mice with aging were suppressed by TI-31 when administered orally 5 times per week for 16 weeks at doses of 2, 10, or 50 mg/kg. It suppressed proteinuria, oliguria, the decrease of erythrocyte count, and increase of serum urea nitrogen, immune complex and anti-double-stranded DNA antibody levels. The anti-nephritic effect of TI-31 was confirmed by histopathological evaluation. TI-31 (10 mg/kg) could improve both the elevated polyclonal B cell activation and the depressed antibody response to sheep red blood cells in B/W mice, in comparison with age- and sex-matched BALB/c mice, without any effect on the antibody response in these normal mice. These findings indicate that TI-31 may inhibit B/W nephritis by regulating the antibody production through a mechanism different from that of anti-inflammatory drugs or immunosuppressants.

1,25-Dihydroxyvitamin D3 and 1,24-dihydroxyvitamin D3 suppress in vitro antibody response to T cell-dependent antigen.

1,25-Dihydroxyvitamin D3 and 1,24-dihydroxyvitamin D3 suppressed an antibody response to sheep red blood cells (SRBC, T cell-dependent antigen) by murine splenocytes, in concentrations ranging from 10(-10)-10(-7)M. These suppressive effects were markedly abrogated when T cell-depleted lymphocytes were cultured in the presence of a supernatant of concanavalin A-stimulated spleen cells. On the contrary, neither of them suppressed antibody response to trinitrophenyl-lipopolysaccharide (T cell-independent antigen). These results suggest that the suppressive effect of active vitamin D3 on anti-SRBC response was mediated by the inhibition of T cells.

Abnormality of the delayed type hypersensitivity (DTH) response to Bordetella pertussis in spontaneously hypertensive rats (SHR).

The delayed type hypersensitivity (DTH) response of spontaneously hypertensive rats (SHR) was compared with that of Wistar Kyoto rats (WKY), a normotensive strain. SHR showed a lower DTH response to Bordetella pertussis than WKY, especially 48 to 72 hr after antigenic challenge. These results were observed before appearance of abnormality of antibody formation or blood pressure. The reduced DTH responses of SHR were partially restored by either transfer of WKY thymocytes or treatment with levamisole. Conversely, the transfer of SHR thymocytes into WKY rats tended to diminish the DTH response. These findings suggest that SHR have a disfunction of T lymphocytes involved in DTH response (e.g., increase of suppressor cells and/or decrease of helper cells).