Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice.

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h post-treatment. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than anxiolytic effects.

Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice.

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT 2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic-and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice 24 h post-treatment. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than an anxiolytic effects.

Arteriosclerosis Derived from Cutaneous Inflammation Is Ameliorated by the Deletion of IL-17A and IL-17F.

The skin is one of the major immune organs producing large amounts of proinflammatory and inflammatory cytokines in response to internal or exogenous stimuli, inducing systemic inflammation in various internal organs. In recent years, organ damage associated with inflammatory skin diseases such as psoriasis and atopic dermatitis has received increasing attention, and vascular disorder such as arteriosclerosis is one of the serious complications of chronic inflammatory skin diseases. However, the detailed mechanism of arteriosclerosis in dermatitis and the role of cytokines have not been clarified so far. In the current study, using a spontaneous dermatitis model, we investigated the pathophysiology of arteriosclerosis and the treatment option for inflammatory skin conditions. We employed spontaneous dermatitis model mice overexpressing human caspase-1 in the epidermal keratinocyte (Kcasp1Tg). The thoracic and abdominal aorta was investigated histologically. GeneChip and RT-PCR analysis were performed to measure the changes in mRNA levels in the aorta. To elucidate the direct effect on the artery by major inflammatory cytokines, endothelial cells, vascular smooth muscle cells, and fibroblast cells were co-cultured with several cytokines, and mRNA expression levels were measured. In order to observe the efficacy of IL-17A/F in arteriosclerosis, cross-mating with IL-17A, IL-17F, and IL-17A/F deficient mice was performed. Finally, we also measured snap tension in the abdominal aorta in WT, Kcasp1Tg, and IL17A/F-deficient mice. Kcasp1Tg showed a decrease in the diameter of the abdominal aorta compared to wild-type mice. mRNA levels for six genes including Apol11b, Camp, Chil3, S100a8, S100a9, and Spta1 were increased in the abdominal aorta of Kcasp1Tg. Some of the above mRNA levels were also increased in the co-culture with major inflammatory cytokines, IL-17A/F, IL-1ß, and TNF-α. Dermatitis improved and mRNA levels were partially ameliorated in Kcasp1Tg with IL-17A/F deletion. Arterial fragility was also evidenced in the inflammatory model, but arterial flexibility was revealed in the IL-17A/F deletion model. Severe dermatitis is closely related to secondary arteriosclerosis caused by the persistent release of inflammatory cytokines. The results also proved that treatment against IL-17A and F may ameliorate arteriosclerosis.

Treatment Strategy for Pyoderma Gangrenosum: Skin Grafting with Immunosuppressive Drugs.

Pyoderma gangrenosum (PG) is a relatively rare neutrophilic dermatosis presenting as a rapidly progressive and painful skin ulcer characterized by undermined borders and peripheral erythema. Immunosuppressive therapy is the first-line treatment for PG; however, large ulcers often take months or years to heal. Surgical treatments, such as negative pressure wound therapy (NPWT) and skin grafting, are still controversial due to the risk of inducing the pathergy phenomenon and eliciting PG development by traumatic factors. Herein, we report on four cases of PG treated with skin grafting, with or without NPWT, under the control of immunosuppressive drugs at our institution. All cases adapted well, but one case showed recurrence at the periphery of the grafted area five months postoperatively. The current patients were treated with the following doses of oral prednisolone (PSL): PSL 10 mg daily, PSL 5 mg daily + adalimumab 40 mg/week, PSL 12 mg + 6 mg of tacrolimus daily, and PSL 20 mg daily during skin grafting. No severe complications, including infections, were observed. Surgical treatments, such as skin grafting with or without NPWT, may accelerate wound healing, shorten the administration of analgesics and long-term immunosuppressive therapy, and reduce the risk of infection.

IL-17A Is the Critical Cytokine for Liver and Spleen Amyloidosis in Inflammatory Skin Disease.

Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.

Severe skin inflammation leads to salivary gland atrophy and dysfunction.

Psoriasis and atopic dermatitis are inflammatory skin diseases, and these patients have an increased risk of cardiovascular events and other medical complications. It has been clarified that skin inflammation affects internal organs. Additionally, dental caries tends to occur more frequently in patients with psoriasis and atopic dermatitis. In this study, we aim to investigate the effects of dermatitis on the salivary glands using an inflammation model mouse. Salivary secretion stimulated with pilocarpine was reduced in dermatitis mice. Histologically, dermatitis mice showed amyloid deposition, glandular atrophy, and fibrosis in the salivary glands. Expression of inflammatory cytokines in the salivary glands was higher in dermatitis mice; however, secretion of cytokines in saliva was not significantly different. Dermatitis mice showed decreased salivary secretion and histological changes, which may cause periodontal disease. Therefore, appropriate control of skin inflammation is essential.

The clinical significance of a shortened activated partial thromboplastin time in patients with connective tissue disease.

INTRODUCTION: Connective tissue disease (CTD) patients have been reported to have an increased risk of venous thromboembolism (VTE). Deep venous thrombosis represents a potential emergency that may have a fatal outcome. The D-dimer test is the most widely accepted screening marker for VTE; however, elevation of the plasma D-dimer level without demonstrable thrombosis sometimes accompanies CTD activity itself, infection, and other conditions. Thus, the accuracy of a diagnosis of VTE based on a D-dimer test result is lower in CTD patients. The activated partial thromboplastin time (APTT) test is a very common and simple test. METHOD: The medical records of 535 CTD patients were retrospectively investigated. The following data were extracted: APTT, D-dimer, thrombotic events, laboratory data, and systemic corticosteroid therapy. RESULTS: The rates of thrombotic events and VTE were significantly increased in patients with a shortened APTT (< 26 s) (PSAPTT) in comparison to those without a shortened APTT (p = 0.004, 0.0009, respectively). The number of PSAPTTs was significantly increased in patients with VTE in comparison to those without VTE (p = 0.0009). In the diagnosis of VTE in CTD patients, the specificity and positive predictive value (PPV) of the D-dimer test were 71.6% and 83.8% and 12.7% and 19.4%, respectively. The combination of a shortened APTT and elevated plasma D-dimer level improved the specificity and PPV to 94.7% and 97.3% and to 25.0% and 36.4%, respectively. CONCLUSIONS: For the evaluation of possibility of accompanying VTE in CTD patients, APTT shortened was useful and should be evaluated with careful attention. KEY POINTS: • Regarding the specificity for diagnosing VTE in CTD patients, a shortened APTT showed a value (84.3%) comparable or superior to that of the D-dimer test. • The combination of a shortened APTT and elevated D-dimer level improved the specificity of the diagnosis of VTE in CTD patients to (94.7% or 97.3%) in comparison to the D-dimer test alone (71.6% or 83.8%). • The positive predictive value of the combination of a shortened APTT and plasma D-dimer elevation for the diagnosis of VTE in CTD patients increased to 25.0% or 36.4%. • In the management of CTD patients, physicians should pay attention when they encounter patients with a shortened APTT, as it may indicate VTE.