Acute Ischemic Stroke

Ischaemic Stroke

Ischaemic stroke (IS) is an acute neurological dysfunction of vascular origin corresponding to the deprivation of blood supply to the brain cells. Progression of inflammation and immune activation plays a complex role in the development, severity, and outcome of IS. It has been shown that effectors of the innate immune system such as the complement system are activated by brain ischemia and tissue damage, leading to the amplification of the inflammatory cascade.

Role of Lectin Pathway in Ischaemic Stroke

The lectin pathway is initiated by the binding of the recognition molecules mannose-binding lectin (MBL) or ficolins to carbohydrates on the surfaces of pathogens. In recent years, there is growing evidence suggesting that the lectin pathways are involved in the progression and outcome of IS. For example, complement activation by natural IgM has been shown to occur in organ models of ischemia/reperfusion injury (IRI), with IgM-mediated activation occurring via the lectin pathway. Moreover, a role for the lectin pathway was also indicated in cerebral IRI, since lectin pathway deficiency is protective in murine models. Clinically, in 353 patients with acute IS, low MBL levels were found to be associated with smaller cerebral infarct volume and favorable outcome after 3 months.

Systemic sclerosis.

Fig.1 Schematic diagram of the triggers of complement activation after cerebral ischemia-reperfusion injury. (Alawieh, 2015)

Introduction of MASP-1

The recognition molecules are capable of binding to the so-called MBL-associated serine proteases (MASPs), leading to the conformational changes and autoactivation of MASPs. Among the MASPs, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate and then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 is also capable of interacting with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

Role of MASP-1 in Ischemic Stroke

In 2013, Frauenknecht et al. observed clinically that MASP-1 levels were highest in patients with subacute MI and lowest in stroke patients. Moreover, in a recently published article, results have suggested that the complement lectin pathway serine proteases, MASP-1 and MASP-2, may be associated with IS development risk and may participate in pathological events leading to post-ischemic brain damage. In addition to these findings, the suitability of serine proteases to be the drug targets has also been discovered. As a result, great efforts have been made on the development of protease inhibitors. Since the US FDA’s approval of the first complement-specific drug against complement component C5 (eculizumab; Soliris), in March 2007, many other promising drug candidates and therapeutic strategies are currently in the pipeline of various companies.

Creative Biolabs, as a trustworthy research partner, is an industry leader in the field of biopharmaceutics development, and it has established advanced Complement Therapeutics Platform to provide antibody, protein, small molecule drug development services for the treatment of a range of diseases caused by excessive or uncontrolled activation of the complement system. Please contact us for detailed information.

Reference
1. Alawieh, A.; et al. Complement in the homeostatic and ischemic brain. Frontiers in immunology. 2015, 12;6:417.

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Questions & Answer

A: The complement system is an important component of innate immunity and usually provides protection by eliminating pathogens and accumulating debris. However, the defensive function of the complement system exacerbates immune, inflammatory, and degenerative responses in a variety of pathological conditions. Accumulating evidence suggests that the complement system plays a key role in the pathogenesis of ischemic brain injury, as depletion of certain complement components or inhibition of complement activation can attenuate ischemic brain injury. Thus, multiple candidates that modulate or inhibit complement activation show great potential for the treatment of ischemic stroke.

A: Dysregulated or over-activated complement activation is associated with ischaemic stroke pathological conditions. Therefore it can be considered a therapeutic option in drug discovery. A number of complement-targeted therapies have been developed to modulate complement activation and mitigate tissue damage. Several drugs that inhibit all or part of the complement system, such as C1 inhibitors, CVF, C3aR antagonists, and C5aR antagonists, may reduce ischemic/reperfusion brain injury.

A: First, since several components such as C1q, C3 and C3aR are involved in synaptic plasticity and neurogenesis under both normal and stroke conditions, a more specific and focused complement regulation must be selected, which may lead to fewer adverse complications. Second, traditional small molecule or biological approaches must be used to modulate the complement system. The last is to link the discovery of changes in complement composition to the effector mechanisms leading to tissue damage in experimental and clinical ischemic strokes.

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