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Updated: Aug 18, 2026
A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia
Published on: August 18, 2015
Therapeutic potential of TACE inhibitors in stroke
1Wyeth Research, Cambridge, MA 02140, USA.
Insights
Targeting tumor necrosis factor-alpha (TNF-alpha) with TACE/MMP inhibitors shows promise for treating stroke. These small molecules may offer a valuable alternative to current therapies, addressing limitations of existing treatments.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Stroke is a leading cause of death and disability, with limited effective treatments beyond the early window for rt-PA.
- Inflammation, particularly involving tumor necrosis factor-alpha (TNF-alpha), plays a critical role in stroke pathogenesis.
- Existing anti-TNF biologics are effective for other inflammatory diseases, validating TNF-alpha as a therapeutic target.
Purpose of the Study:
- To review the role of TNF-alpha in stroke.
- To evaluate the therapeutic potential of TACE/MMP inhibitors in preclinical stroke models.
- To explore small molecule inhibitors as an alternative to protein therapeutics for stroke.
Main Methods:
- Review of preclinical studies investigating TNF-alpha pathways in stroke.
- Analysis of the efficacy of TACE/MMP inhibitors in various stroke models.
- Discussion of the limitations of current stroke therapies and the potential of novel inhibitors.
Main Results:
- TNF-alpha is implicated in the induction and progression of ischemic stroke.
- Anti-TNF biologics have demonstrated efficacy in preclinical stroke models.
- TACE, as the key sheddase for TNF-alpha, represents a viable target for small molecule inhibitors.
Conclusions:
- TACE/MMP inhibitors show significant therapeutic potential for stroke treatment.
- Small molecule TNF-alpha inhibitors offer a promising alternative to protein therapeutics.
- Targeting TACE/MMP could provide valuable new therapeutic options for stroke patients.
Abstract:
Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.
