Therapeutic capabilities of naturally-derived p38 MAPK inhibitors for protecting the cerebrovascular system in severe SARS‑CoV‑2 infection

In COVID‑19, hyper‑inflammatory responses are associated with increased p38 MAPK activity, which may arise from the loss of ACE2 following SARS‑CoV‑2 infection. Emerging evidence also suggests that SARS‑CoV‑2 may exploit p38 MAPK signaling to enhance viral replication. Collectively, these observations indicate that appropriate modulation of the p38 MAPK pathway represents a rational strategy for both inhibiting SARS‑CoV‑2 replication and attenuating hyper‑inflammatory immune responses in severe COVID‑19. Furthermore, dysregulated activation of this pathway can induce cerebro‑vasoconstriction, potentially contributing to severe neurological complications such as intracerebral hemorrhage (ICH), cerebral venous thrombosis (CVT), and stroke. Consequently, BBB‑penetrating p38 MAPK modulators may offer therapeutic benefits for high‑risk COVID‑19 patients with CNS complications, particularly those involving cerebrovascular dysfunction. This review explores the therapeutic potential of recently identified naturally derived p38 MAPK inhibitors with BBB‑penetrating properties (including some flavonoids, isoquinoline alkaloids, tanshinones, coumarins, and structurally diverse miscellaneous compounds) in managing cerebral vasoconstriction and related complications during severe COVID‑19. Our findings suggest that BBB‑penetrating p38 MAPK inhibitors hold considerable promise as supplements or adjuvants to mitigate the risks associated with cerebral vasoconstriction in COVID‑19 patients.