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BR-102024017973-A2 - Use of LQB 118 for the treatment of inflammation.

BR102024017973A2BR 102024017973 A2BR102024017973 A2BR 102024017973A2BR-102024017973-A2

Abstract

Inflammation is a physiological response to damaging stimuli, whether infectious or not. It consists of a series of cellular and molecular mechanisms that culminate in the reestablishment of the body's homeostasis. In the initial phase of inflammation, macrophages perform various functions, such as phagocytosis and the production of various inflammatory cytokines. Although considered a defense response of the body, the inflammatory process can become pathological when dysregulated, being a determining factor in the development of many diseases, including cancer. Many drugs are available for the treatment of inflammation; however, most of them have numerous side effects, as well as other risks when used for long periods of time. Within this context, the search for new pharmacological tools for the control of inflammation that are safer and more effective becomes necessary. The invention described herein claims the pharmacological effect of LQB 118 for the treatment of inflammation, given that experimental results have demonstrated that this molecule exhibited anti-inflammatory potential in an experimental model of zymosan-induced peritonitis and in murine peritoneal macrophage cultures stimulated with zymosan.

Inventors

  • SANDRA RODRIGUES MASCARENHAS
  • ÉSSIA DE ALMEIDA LIMA
  • LUIZ HENRIQUE AGRA CAVALCANTE SILVA
  • DEYSE CRISTINA MADRUGA CARVALHO
  • Chaquip Daher Netto
  • PAULO ROBERTO RIBEIRO COSTA

Assignees

  • UNIVERSIDADE FEDERAL DA PARAIBA
  • UNIVERSIDADE FEDERAL DA RIO DE JANEIRO

Dates

Publication Date
20260317
Application Date
20240830

Claims (9)

  1. 1) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 inhibits neutrophil migration in the zymosan-induced peritonitis model.
  2. 2) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces IL-1β cytokine levels in a zymosan-induced peritonitis model.
  3. 3) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces IL-6 cytokine levels in a zymosan-induced peritonitis model.
  4. 4) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 does not interfere with the viability of peritoneal macrophages stimulated with zymosan.
  5. 5) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces the levels of the cytokine IL-1β in peritoneal macrophages stimulated with zymosan.
  6. 6) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces the levels of the cytokine IL-6 in peritoneal macrophages stimulated with zymosan.
  7. 7) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces the expression of TLR2 in peritoneal macrophages stimulated with zymosan.
  8. 8) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces the expression of CD69 in peritoneal macrophages stimulated with zymosan.
  9. 9) “USE OF LQB 118 FOR THE TREATMENT OF INFLAMMATION” characterized by the fact that LQB 118 reduces the phosphorylation of MAPK p-38 in peritoneal macrophages stimulated with zymosan.

Description

[001] The present invention relates to the use of LQB 118 for the treatment of inflammation. [002] LQB 118 is a synthetic hybrid molecule with a structure based on two groups of bioactive molecules: pterocarpans and quinones. Both groups have several reported biological activities, including anti-inflammatory activity. [003] Inflammation is the body's response to damaging stimuli, whether infectious or not. It consists of a series of cellular and molecular events that culminate in the elimination of pathogens or damaged tissues and restore the body's homeostasis. In the initial phase of inflammation, neutrophils and macrophages perform various functions, such as the production of mediators and phagocytosis. [004] The inflammatory process, although beneficial to the body by restoring lost homeostasis, is associated with the development and maintenance of many diseases once it becomes dysregulated. [005] There are many drugs available for the treatment of inflammatory conditions; however, most of them have side effects and various risks when used for extended periods of time. Therefore, it is necessary to search for new molecules that can beneficially interfere with the inflammatory process and that are safer and more effective. [006] LQB 118 (molar mass: 304.3 g/mol; molecular formula: C19H12O4) was synthesized at UFRJ. A stock solution (5 mg/mL) was solubilized in dimethyl sulfoxide (DMSO) and diluted in RPMI-1640 medium or water for injection for the execution of in vitro and in vivo experiments, respectively. [007] The invention described herein claims the pharmacological effect of LQB 118 for the treatment of inflammation characterized by the fact that LQB 118 exhibits anti-inflammatory potential in an experimental model of murine peritoneal macrophage culture stimulated with zymosan and zymosan-induced peritonitis. [008] LQB 118 at concentrations of 5, 1, 0.5 and 0.1 μM does not affect the viability of murine peritoneal macrophages. Thus, it is concluded that the anti-inflammatory effect of the molecule is not associated with cytotoxicity. [009] LQB 118 reduces the levels of the pro-inflammatory cytokines IL-1β and IL-6 in the supernatant of murine peritoneal macrophage cultures stimulated with zymosan. [010] LQB 118 reduces the expression levels of Toll-like receptor type 2 in murine peritoneal macrophages stimulated with zymosan. Since this is the zymosan receptor, the fact that LQB 118 reduces its expression indicates the anti-inflammatory effect of this molecule. [011] LQB 118 reduces the expression of the activating molecule CD69, which is capable of triggering intracellular signaling cascades that lead to the production of cytokines, chemokines, adhesion molecules, and other pro-inflammatory mediators in murine peritoneal macrophages stimulated with zymosan. The decrease in CD69 expression may partially explain the reduction in cytokines observed with LQB 118 treatment. [012] LQB 118 is additionally able to reduce MAPK p-38 phosphorylation in murine peritoneal macrophages stimulated with zymosan. Since TLR2 transmits the agonist recognition signal and thus stimulates cytokine production, the anti-inflammatory effect of LQB 118 can also be demonstrated by this reduction. [013] LQB 118 at doses of 10 and 20 mg/kg is able to reduce neutrophil migration into the peritoneal cavity of Swiss mice in a zymosan-induced peritonitis model. Since neutrophil migration is a fundamental event for the development of the inflammatory response, the fact that LQB 118 reduces this neutrophil infiltration indicates its anti-inflammatory effect. [014] LQB 118 at doses of 10 and 20 mg/kg is also able to reduce the levels of cytokines IL-1β and IL-6 in peritoneal lavage in a zymosan-induced peritonitis model, which may be associated with a decrease in the number of neutrophils in this lavage, since these cells are the main producers of mediators, including cytokines, in this model. Additionally, these data reinforce the anti-inflammatory potential of LQB 118. [015] The invention can be better understood through the attached figures relating to the results obtained in the experiments. [016] FIGURE 1 shows the chemical structure of LQB 118. [017] FIGURE 2 shows the effect of LQB 118 on neutrophil migration in the zymosan-induced peritonitis model. [018] FIGURE 3 shows the effect of LQB 118 on IL-1β cytokine levels in a zymosan-induced peritonitis model. [019] FIGURE 4 shows the effect of LQB 118 on IL-6 cytokine levels in a zymosan-induced peritonitis model. [020] FIGURE 5 shows the effect of LQB 118 on the viability of peritoneal macrophages stimulated with zymosan. [021] FIGURE 6 shows the effect of LQB 118 on IL-1β cytokine levels in peritoneal macrophages stimulated with zymosan. [022] FIGURE 7 shows the effect of LQB 118 on IL-6 cytokine levels in peritoneal macrophages stimulated with zymosan. [023] FIGURE 8 shows the effect of LQB 118 on TLR2 expression levels in peritoneal macrophages stimulated with zymosan. [024]