Nrf2 modulators(Nuclear factor erythroid 2-related factor 2 modulators), STAT3 modulators(Signal transducer and activator of transcription 3 modulators)

Therapeutic Areas

NeoplasmsImmune System DiseasesEndocrinology and Metabolic Disease+ [2]

Active Indication

Polycystic Ovary SyndromeAutoimmune DiseasesUveitis

Inactive Indication-

Originator Organization-

Active Organization

Tianjin Medical University

Second Hospital of Tianjin Medical University

Shahid Chamran University of Ahvaz

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with Dimethyl itaconate

100 Translational Medicine associated with Dimethyl itaconate

100 Patents (Medical) associated with Dimethyl itaconate

Literatures (Medical) associated with Dimethyl itaconate

01 Nov 2023·Biomedicine & Pharmacotherapy

Itaconate: A promising precursor for treatment of neuroinflammation associated depression

Review

Author: Cao, Yemin ; Gong, Yueling ; Zhou, Mingmei ; Xia, Chenyi ; Zhao, Cheng ; Liu, Ruisi

Neuroinflammation triggers the production of inflammatory factors, influences neuron generation and synaptic plasticity, thus playing an important role in the pathogenesis of depression and becoming an important direction of depression prevention and treatment. Itaconate is a metabolite secreted by macrophages in immunomodulatory responses, that has potent immunomodulatory effects and has been proven to exert anti-inflammatory effects in a variety of diseases. Microglia are mononuclear macrophages that reside in the central nervous system (CNS), and may be the source of endogenous itaconate in the brain. Itaconate can directly inhibit succinate dehydrogenase (SDH), reduce the production of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), activate nuclear factor erythroid-2 related factor 2 (Nrf2), and block glycolysis, and thereby improving the depressive symptoms associated with the above mechanisms. Notably, itaconate also indirectly ameliorates the depressive symptoms associated with some inflammatory diseases. With the optimization of the structure and the development of new delivery systems, the application value and therapeutic potential of itaconate have been significantly improved. Dimethyl itaconate (DI) and 4-octyl itaconate (4-OI), cell-permeable derivatives of itaconate, are more suitable for crossing the blood-brain barrier (BBB), exhibiting therapeutic effects in the research of multiple diseases. This article provides an overview of the immunomodulatory effects of itaconate and its potential therapeutic efficacy in inflammatory depression, focusing on the promising application of itaconate as a precursor of antidepressants.

01 Jul 2021·Brain Communications

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia

Article

Author: Kuo, Ping-Chang ; Weng, Wen-Tsan ; Scofield, Barbara A ; Yen, Jui-Hung ; Paraiso, Hallel C ; Furnas, Destin ; Yu, I-Chen

AbstractInflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood–brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1−/− stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke.

PLOS ONE

The protective effect of DMI on hippocampus EEG, behavioral and biochemical parameters in hypoxia-induced seizure on neonatal period

Article

Author: Nazarizadeh, Shadi ; Ghotbeddin, Zohreh ; Ghafouri, Samireh ; Sarkaki, Alireza

Hypoxia-Induced Neonatal Seizure (HINS) is a prevalent type of seizure in infants caused by hypoxic conditions, which can lead to an increased risk of epilepsy, learning disabilities, and cognitive impairments later in life. This study focuses on examining the effects of dimethyl itaconate (DMI) on cognition, motor coordination, and anxiety-like behavior in male rats that have experienced HINS. 42 male Wistar newborn rats (PND10) were randomly divided into six groups (n = 7). 1) Control (Vehicle only); received DMI solvent (0.1ml) without applying hypoxia. 2–3) DMI; receiving (20 and 50 mg/kg; i.p). 4) HINS; they were placed in a hypoxia chamber with 7% oxygen and 93% nitrogen concentration for 15 minutes. 5–6) DMI+HINS; received DMI (20 and 50 mg/kg; i.p) 24h before hypoxia. Behavioral tests including; Novel object recognition test, Rotarod, Parallel bar, Open field and elevated plus maze (EPM); started at age 45 after birth. After behavioral tests, the hippocampal CA1 region local EEG was recorded in all groups. Then the brain hippocampus tissue was isolated and the amount of MDA, SOD, NO, and Thiol was measured by ELISA method. Data showed that the administration of DMI improved motor symptoms, anxiety-like behaviors, and cognition in HINS rats (p<0.05). EEG power in the HINS group decreased significantly compared to other experimental groups (p<0.05). Biochemical observations showed that DMI significantly reduced oxidative stress and inflammation in the hippocampal tissue of HINS rats (p<0.05). Increased hippocampal oxidative stress and inflammation can be effective in the occurrence of behavioral disorders observed in HINS rats. While DMI improved these behavioral impairments by reducing oxidative stress and inflammation.

100 Deals associated with Dimethyl itaconate

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Polycystic Ovary Syndrome	Preclinical	IR	Shahid Chamran University of Ahvaz	01 Oct 2024
Autoimmune Diseases	Preclinical	CN	Tianjin Medical University	06 Apr 2024
Autoimmune Diseases	Preclinical	CN	Second Hospital of Tianjin Medical University	06 Apr 2024
Uveitis	Preclinical	CN	Second Hospital of Tianjin Medical University	06 Apr 2024
Uveitis	Preclinical	CN	Tianjin Medical University	06 Apr 2024

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