Senescence-Accelerated Mouse (SAM) has been under development by our research team at Kyoto University since 1970, based on the AKR/J strain donated by the Jackson Laboratory in 1968. The SAM mouse has an accelerated senescence and age-associated pathologies such as senile amyloidosis, senile osteoporosis, degenerative joint disease, cataract, deficits in learning and memory, brain atrophy, hyperinflation of lungs, hearing impairment and so on. SAM research is advancing world-wide and attempts are being made to clarify fundamental mechanisms involved in primary aging processes, pathogenesis of age-associated pathologies and effective methods to modulate or ameliorate the advance of senescence and disease processes involved in age-associated pathologies.

Journal Article↗

PubMedDate not supplied

FK506 induces the atrophy of enteric ganglia in small bowel transplantation, which can be prevented by the neuropeptide bombesin.

PURPOSE: FK506, which is widely used for immunosuppression, is reported to have neurotoxicity. However, its neurotoxicity for transplanted graft enteric ganglia (TGEG) has never been reported. The aim of this study was to investigate whether FK506 has a neurotoxic effect on TGEG, and whether bombesin (BBS) prevents such atrophy. METHODS: Eighteen rats that underwent syngertic heterotopic small bowel transplantation (SBTx) using a cuff method were divided into three groups of six rats each; A: SBTx alone, B: SBTx with FK506, C: SBTx with FK506/BBS. Either BBS (10 mg/kg/d) or normal saline was infused continuously from day 14 to 28. Rats in groups B and C were administered FK506 (0.32 mg/kg/day, intramuscularly) daily. Analysis of TGEG was performed using immunohistochemistry with protein gene product (PGP) 9.5. The ganglionic number was obtained by counting PGP9.5-positive ganglia in each graft. RESULTS: The number of TGEG were reduced significantly in group B (51.5 +/- 7.7 ganglia per cross section (G/CS)) compared with group A (69.7 +/- 6.0 G/CS), but were well preserved in group C (84.8 +/- 10.2 G/CS). There were significant differences between groups B and C (P < .001) and also between groups A and C (P < .001). CONCLUSION: FK506 showed severe neurotoxicity on transplanted grafts, and bombesin could rescue TGEG against FK506 neurotoxicity.

Animals↗

PubMedDate not supplied

Prevention of warm ischemic injury by neuropeptide bombesin in small bowel transplantation.

PURPOSE: This study investigated whether preoperative administration of neuropeptide bombesin (BBS) had a protective effect against IR/I and subsequent acute rejection. METHODS: Allogeneic SBTx was performed heterotopically in rats (n = 18). That were administered FK506 (0.32 kg/d) daily. The rats were divided into three groups of six rats each: group 1, BBS(-)5: warm ischemic time (WIT); 5 minutes without BBS; group 2, BBS(-)15: WIT; 15 minutes without BBS; group 3, BBS(+)15: WIT; 15 minutes with BBS. The specimens were obtained from the stoma site at 1 hour after reperfusion and on postoperative days (PODs) 1 and 7. The graft mucosal state and degree of acute rejection were evaluated by H and E staining. The apoptotic cells in the crypt lesion were evaluated using TUNEL immunohistochemistry. An apoptotic index (AI) was calculated for quantitative analysis. RESULTS: H and E staining revealed that on POD 1 the mucosal villi were shortened in the BBS(-)15 group compared with the other two groups. One hour after reperfusion, the AI in BBS(-)15 group was 125.0 per thousand +/- 37.2 per thousand, which was significantly higher (P < .05) than that in the BBS(-)5 group (32.6 per thousand +/- 5.0 per thousand) or the BBS(+)15 group (32.0 per thousand +/- 3.0 per thousand). On POD 7, the AI in the BBS(-)15 group was 63.7 per thousand +/- 5.03 per thousand, which was significantly higher (P < .05) than in the BBS(-)5 (17.3 per thousand +/- 4.6 per thousand) or the BBS(+)15 group (12.3 per thousand +/- 3.06 per thousand). CONCLUSIONS: Even a short WIT of 15 minutes induced considerable allograft mucosal damage, which also heightened the possibility of acute rejection. Exogenous BBS prevented mucosal damage by IR/I and was also beneficial to prevent acute rejection.

Animals↗

PubMedDate not supplied

Neuroendocrine-immune modulation may be useful for allograft-specific immunosuppression in small bowel transplantation.

PURPOSE: The authors have previously demonstrated that the neuropeptide bombesin (BBS) prevented allograft mucosal atrophy under tacrolimus (TRL) immunosuppression for rats small bowel transplantation (SBT). The present study investigated whether BBS had immunosuppressive effects on small bowel allografts. METHODS: Allogeneic SBT was performed heterotopically in rats (n = 12) that received daily administration of 0.1 mg/kg/d TRL from postoperative day 0 to day 14. Rats divided into two groups of six rats each were administered BBS or normal saline as a control. Biopsy of the allograft was performed from the stomal site on postoperative days 6, 10, and 14. The state of the graft mucosal villi was evaluated by H & E staining and TUNEL immunohistochemistry. RESULTS: By postoperative day 14, extensive mucosal destruction accompanied by heavy transmural cellular infiltration had developed in the control group. Lymphocytes and plasma cells infiltrated the lamina propria of the allograft without the distorting villous architecture in the BBS group. The TUNEL index of graft mucosa in the control group was 1.26% +/- 0.37% (mean +/- SD) and that in the BBS group, 0.59% +/- 0.20%, respectively (p < .001). CONCLUSION: This study demonstrated an immunosuppressive effect of bombesin on transplanted allografts, which might dramatically reduce the dose of TRL required for postoperative immunosuppression.

Amino Acids↗

PubMedDate not supplied

Deterioration in learning and memory of fear conditioning in response to context in aged SAMP8 mice.

This study examined age-dependent deficits in the learning and memory of fear conditioning, using a newly developed senescence-accelerated mouse (SAMP8) model of age-related brain dysfunction and its genetically related inbred strain (SAMR1). The mice were classically conditioned to tone by giving aversive foot shocks in a distinct experimental box (context). After conditioning, fear in response to the original context without the tone and to the tone in a different context were tested with no shocks. Freezing behavior was used as a reliable index of fear. At 4 and 8 months, contextual fear was weaker in the accelerated senescence-prone SAMP8 mice than in the accelerated senescence-resistant SAMR1 mice. However, at 1 and 2 months, both SAMP8 and SAMR1 mice showed significant contextual fear to equivalent levels. Aging did not affect the fear response to tone. These results indicate that SAMP8 mice have age-related learning and memory deficits in their fear response evoked by contextual but not explicit tone stimuli. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in contextual fear conditioning in SAMP8 mice.

Aging↗

PubMedDate not supplied

Senescence-accelerated mouse (SAM): a novel murine model of senescence.

The Senescence-Accelerated Mouse (SAM) has been under development by our research team at Kyoto University since 1970 through the selective inbreeding of the AKR/J strain of mice donated by the Jackson Laboratory in 1968, based on a graded score for senescence, life span, and pathologic phenotype. At present, there are 12 lines of SAM: nine senescence-prone inbred strains (SAMP) including SAMP1, SAMP2, SAMP3, SAMP6, SAMP7, SAMP8, SAMP9, SAMP10, and SAMP11; and three senescence-resistant inbred strains (SAMR) including SAMR1, SAMR4, and SAMR5. Data from survival curves, Gompertzian function, and grading score of senescence, together with growth patterns of body weight of these SAMP and SAMR, revealed that the characteristic feature of aging common to all SAMP mice is "accelerated senescence;" early onset and irreversible advance of senescence manifested by several signs and gross lesions such as the loss of normal behavior, various skin lesions, increased lordokyphosis, etc., after a period of normal development. In the course of SAM development, it became evident that SAMP strains manifest various pathologic phenotypes that are characteristic enough to differentiate the SAM strains. The genetic background and significance of SAM development are discussed.

Aging↗

PubMedDate not supplied

Genetic characterization of senescence-accelerated mouse (SAM).

The Senescence-Accelerated Mouse (SAM) strains are unique and appropriate models for genetic studies on aging because the SAMP strains have an "accelerated senescence" phenotype for which the SAMR strains are controls, and each SAMP strain has a strain-specific age-associated disorder. Furthermore, because they have gone through sufficient generations of sister-brother mating, they can be considered inbred strains, which can be analyzed genetically. There are now 11 SAMP strains and 3 SAMR strains descended from the progenitor litters. Analysis with the Gompertz function shows that the SAMP strains have the same initial mortality rate (IMR) as the SAMR strains but a shorter mortality rate doubling time (MRDT), presumably due to genes that accelerated the rate of senescence in the SAMP strains. This accelerated senescence may also occur in cultured fibroblast-like cells. We performed molecular genetic characterization of all the SAM strains to acquire a base of genetic information from which we could develop hypotheses on the mechanism of development of SAM strains and genetic factors that contribute to accelerated senescence.

Aging↗

PubMedDate not supplied

Neuropathological studies on strains of senescence-accelerated mice (SAM) with age-related deficits in learning and memory.

In a series of inbred Senescence-Accelerated mice (SAM) strains, accelerated-senescence prone SAMP substrains show early onset and rapid advancement of senescence. SAMP8 and SAMP10, in particular, exhibit a significant age-related deterioration in memory and learning for passive and active avoidance tasks with, respectively, a low and high incidence of systemic senile amyloidosis. In the brains of both SAMP8 and SAMP10 strains, we have found numerous morphological alterations. Here we review the changes seen in both neuronal or glial components in SAMP8/P10 brains. They may serve as markers of the neuronal degeneration leading to the deficits in learning and memory.

Aging↗