Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Female Wistar rats were trained in a Skinner-box, 30 trials per day in a dark room to establish operant defence conditioning. Training started with a light (15 s), then combined with footshock for further 8 s. When the rats learned to press the key to avoid footshock within 15 s, conditioned response was considered established. After the rats reached a conditioning rate (CR) above 80% for 5 days, cannulae were implanted into caudate-putamen. Two to three days later, Met-enkephalin (MEK) or bestatin (an aminopeptidase inhibitor) was injected bilaterally into caudate-putamen. 30 min, 2 h, 24 h and 48 h after injection, conditioning tests were conducted, with each session consisting of 30 trials. Control experiments were done when 0.9% NaCl (NS) was injected. After injection of NS, CR maintained above 80% in all 4 test sessions. MEK (60 ng/rat) or bestatin (10 micrograms/rat) significantly lowered the CR during the 30 min and 2 h test session. In the latter case, the latency (L) was also prolonged. However both CR and L returned to the control level in the 24 h and 48 h test sessions. Naloxone (2 mg/kg, i.p.) blocked the conditioning-depression effect of bestatin. No significant alteration was seen in locomotor activity after MEK or bestatin injection. The results suggest that enkephalin in caudate-putamen may be involved in the regulation of retrieval of conditioning. Bestatin mimics the effect of MEK on conditioning reflex probably by increasing production of endogenous enkephalin.
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PMID:[Effect of injection of enkephalin and bestatin in caudate-putamen on operant conditioning in rats]. 129 61

The effect of chronic treatment with an immunostimulating agent, bestatin, on age-associated immune decline was assessed in C57BL/6 mice. Animals were given weekly doses of bestatin (100 micrograms/mouse, i.p.) from 7 months of age until death, and immune responses (natural killer cell activity, T cell cytotoxicity in vitro and in vivo, delayed-type hypersensitivity reaction, lymphoproliferative responses to mitogens, production of interleukin-2, macrophage functions) were tested at 11, 15, and 20 months. Most of the functions were reduced in 15-17-month-old mice, but evidence of reduced macrophage activities appeared only in limiting conditions (low lipopolysaccharide stimulation for interleukin-1 production and low concentration of macrophages in the cytostatic test). Bestatin administration produced a transient increase in natural killer (NK) cell activity and in vivo T cell cytotoxicity, followed (15-20 months of age) by a depression of NK and T cell-mediated responses. Only macrophage functions were stimulated in 20-month-old bestatin-treated mice. This unresponsiveness coincides with an accelerated mortality of bestatin-treated mice and a significant increase in the number of spontaneous tumor-bearing animals. The stimulation of T cells by bestatin seems to be mediated by a primary activation of macrophages to release immune mediators. Several reasons for the bestatin-induced immunodepression can be postulated including a high dose of bestatin, leading to toxicity or unresponsiveness; induction of suppressor cells; and overproliferation of T cells due to the mitogenic activity of bestatin, which may act as a promoting factor for tumor development.
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PMID:Acceleration of age-associated immune decline and mortality by early repeated administration of bestatin to C57BL/6 mice. 348 72

In two separate lymphoma populations, we examined immune reconstitution following high dose chemotherapy (HDT) and bone marrow transplantation (BMT). In the first study we followed immune reconstitution for one year after HDT and BMT. In the second study we examined the ability of the orally active immunomodulator, Bestatin to augment immune reconstitution following HDT and BMT. The studies on immune reconstitution following HDT and BMT were undertaken in a cohort of non-Hodgkin's lymphoma (NHL) patients (n = 35) and examined the peripheral blood (PB) leukocyte subsets and their in vitro functions. Our results demonstrate that monocyte and natural killer (NK) cell engraftment occurred more rapidly then did T cell reconstitution. We also observed a significant decrease in the CD4:CD8 ratio post-transplantation as compared to normal PB donors due to a decrease in CD4+ cells. In addition, following HDT and BMT, measures of T cell function (phytohemagglutinin [PHA] mitogenesis) and T helper cell activity (pokeweed mitogen [PWM] mitogenesis) were consistently depressed as compared to cells from normal PB. Further, we demonstrate a correlation between the loss of T cell function and the frequency of circulating monocytes, suggesting a cause-effect relationship. Despite the dysfunction in T cells following HDT and BMT, immune-modulating agents can still augment the immune function. One such drug is Bestatin (ubenimex), an inhibitor of aminopeptidase (AP) that binds to CD13 on macrophage/monocytes. To examine its immune modulatory activity after HDT and BMT, a dose finding (10, 30, 90 and 180 mg/day) phase Ib trial was conducted with 30 Hodgkin's disease (HD) and NHL patients who received no drug (control), or Bestatin daily for 60 days following BMT. In these studies, Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on two consecutive days. These studies revealed that Bestatin significantly increased the PHA and PWM responses in a dose-dependent manner. Flow cytometric analysis revealed a significant increase in NK cells (CD56+), B cells (CD19+), as well as the CD4:CD8 cell ratio. The latter observation was associated largely with a depression in the percent of CD8+ T cells as opposed to an increase in CD4+ T cells. We conclude that despite the peripheral tolerance observed following HDT and BMT, Bestatin could significantly increase some, but not all, immune surrogates.
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PMID:Partial review of immunotherapeutic pharmacology in stem cell transplantation. 1075 81