Secukinumab attenuates neuroinflammation and neurobehavior defect via PKCβ/ERK/NF-κB pathway in a rat model of GMH

Germinal matrix hemorrhage (GMH) is a devastating clinical event for neonates, especially for preterm or low-birth weight infants (Tortora et al., 2018; Ramenghi et al., 2011). Its serious consequences bring relevant social and economic burden to survivors' families (Li et al., 2018). Due to the improvements of diagnostic tools, reproductive technology and intensive care strategies, it could be predictable that the incidence would increase as a result of the delivery of higher numbers of live births, including premature newborns (Xu et al., 2020). Blood components from the ruptured immature vessels are the primary cause of acute and secondary brain injury (Tortora et al., 2018). Hence, survivors suffer from debilitating consequences, such as neurological deficits, post-hemorrhagic hydrocephalus and developmental delay (Tang et al., 2015; Koschnitzky et al., 2018). However, there is no effective management for this severe disease other than prophylactic medications and surgical shunts with significant side effects (Fowlie and Davis, 2003). Therefore, more studies are urgently needed to investigate innovative therapeutic modalities.

The activation of inflammation cascades plays a critical role during the pathological process and aggravates neurobehavioral deficits after GMH (Li et al., 2019; Zhang et al., 2018; Feng et al., 2019). Meanwhile, some inflammatory markers can be seen elevated in the severely hemorrhagic brain (Supramaniam et al., 2013). Inhibition of neuroinflammation is expected to be an effective method to reduce brain injury induced by GMH. Microglia, the main local immune cells, produces inflammatory cytokines and chemokines to elicit neuroinflammation responses (Aronoff et al., 2006; Tang et al., 2016). Mounting studies uncovered that microglia function as an important inflammatory mediator between secondary brain injuries after hemorrhage (Xu, 2021; Brouwer et al., 2016; Zeng et al., 2021).

IL-17 family has 6 members (IL-17A to IL-17F), among which IL-17A is the predominant one with well-studied function (Zhang et al., 2021; Lin et al., 2016). Some evidence has shown that IL-17A is closely associated with neuroinflammation (Park et al., 2020; Shi et al., 2018; Yang et al., 2018). Also, it has been reported that serum IL-17A would increase in hemorrhagic patients and experimental animals (Park et al., 2020; Gao et al., 2020). Previous studies indicated that the protein kinase C beta (PKCβ) could be up-regulated by IL-17A and its receptor (IL-17RA) (Liu et al., 2012). Meanwhile, PKCβ/ERK pathway has been confirmed in many pathologic processes (Bowen et al., 2020; Luan et al., 2020; Zhu et al., 2016). It has been reported that activated ERK is closely related with NF-κB (Ala et al., 2020; Ding et al., 2019a), which plays a pivotal role in inflammation cascades (Durocher et al., 2021; Serra et al., 2020; Wang et al., 2020a). Secukinumab, a recombinant monoclonal antibody (Polat Ekinci et al., 2021), specifically inhibits IL-17A and it is currently used as a treatment for some chronic immune diseases, such as psoriasis and arthritis (Frieder et al., 2018; Mease et al., 2015).

Thus, based on the above described, we hypothesized that the inhibition of IL-17A, via Secukinumab, would potentially reduce neuroinflammation through IL-17RA/PKCβ/ERK/NF-κB pathway in microglia, thereby improving short-term and long-term neurological outcomes after GMH in rats.

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