Ischemic stroke is one of the leading causes of adult death and long-term disability [1], [2]. When ischemic stroke happens, the loss of blood supply leads to a deficiency of oxygen, glucose and lipids, consequently resulting in cerebral parenchyma injury from hours to days [3]. Danger‐associated molecular patterns (DAMPs) are released from the injured cerebral parenchyma to trigger a cascade of inflammatory responses [4]. However, the presence of persistent cerebral parenchyma damage usually brings about excessive neuroinflammation exaggerating secondary brain injury and attenuating neuro-rehabilitation [4], [5]. Microglia, the innate immune cells in the central nervous system (CNS), can be activated in penumbra after ischemic stroke [3]. Once activated, microglia behave as two different phenotypes: the classically activated microglia (M1) and the alternative one (M2) [6]. The deleterious M1 phenotype exhibits a pro-inflammatory reaction characterized by releasing inflammatory cytokines and substances with oxidative properties, such as tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and interleukin-1β (IL-1β) [7]. While, the neuroprotective M2 phenotype exerts an anti-inflammatory effect on promoting the injured cerebral parenchyma repairment via secreting anti-inflammatory agents such as interleukin-4 (IL-4), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) [3]. Meanwhile, M2 phenotype releases a series of neurotrophic factors ameliorating neuroinflammation [8]. Thence, exploring regimens to facilitate microglia transformation from M1 to M2 phenotype is a feasible strategy to suppress neuroinflammation, thereafter reinforcing functional recovery after ischemic stroke.

Muscone, also known as 3-methylpentadecanone, is the main active ingredient of musk. Muscone easily crosses the blood brain barrier (BBB) and distributes throughout the brain to reduce neuronal apoptosis via inhibiting the Fas pathway after stroke in rats [9]. Meanwhile, muscone exerts neuroprotective effect on diabetic peripheral neuropathy through modulating protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway [10], demonstrating that muscone is a neuroprotective agent. Moreover, muscone mitigates cardiac macrophage-mediated chronic inflammation by inhibiting nuclear factor kappa-B (NF-κB) and pyrin-domain-containing 3 (NLRP3) inflammasome activation, thereby improving cardiac function after myocardial infarction (MI) in mice, indicating muscone is a neuroinflammatory mediator. Besides, muscone suppresses microglia activation-mediated inflammatory response through the nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)/janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway and NOD-like receptor protein 3 (NLRP3) inflammasome in a mouse inflammatory pain model [11], showcasing that muscone holds the ability of repressing microglia activation to decrease neuroinflammation. In addition, a review summarizes the underlying mechanisms of muscone exerting multiple protective effect are associated with facilitating cell proliferation, mitigating the loss of cell viability, preventing mitochondrial membrane potential (MMP) collapse, and reducing lactate dehydrogenase (LDH) release, Ca2+ overload, and reactive oxygen species (ROS) generation, as well as decreasing the release of proinflammatory factors, such as IL-1β, TNF-α, prostaglandin E2 (PGE2) and myeloperoxidase (MPO) [12], implying muscone might facilitate microglia transformation into neuroprotective phenotype. However, the role of muscone in mediating microglia polarization and the underlying mechanism are not fully elucidated after ischemic stroke.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand‐activated transcription factor belonging to the nuclear receptor superfamily. PPAR-γ orchestrates the microglial phenotype polarization from M1 to M2 phenotype, thereby suppressing inflammation and boosting tissue repair in various CNS injury such as tissue plasminogen activator (tPA)‐induced brain hemorrhage [13], focal cerebral ischemia [14], pilocarpine-induced status epilepticus [15], and traumatic brain injury (TBI) [16], [17]. Whether PPAR-γ signaling is involved in muscone facilitating microglia transformation is worthy of investigating. Here, we speculated that muscone reinforced microglia polarization into M2 phenotype via activating PPAR-γ following ischemic stroke. The aim of the present study is to provide a therapeutic candidate regulating microglial shift into M2 phenotype for the treatment of ischemic stroke.