Targeting kynurenine pathway and A1 /A2 astrocytes polarization in experimentally induced fibromyalgia: Modulatory role of apigenin on kynurenine/ aryl hydrocarbon receptor signaling.

Abstract

Astrogliosis is thought to be a potential factor in the neuroinflammatory response associated with fibromyalgia (FM); however, the role of A1/A2 astrocyte polarization remains underexplored. Several metabolic processes have been reported to influence astrocyte activation and function. The current study was designed to assess the potential regulatory role of apigenin (API), a natural flavonoid, on astrocytes polarization via modulation of the kynurenine pathway (KP) in rats with FM-like symptoms. Reserpine (Res) (1 mg/kg/day, s.c.) was injected into the rats for three consecutive days to induce FM, after which they were given oral API (25 mg/kg/day) for 14 days. API ameliorated spinal cord degeneration as well as allodynia and hyperalgesia as demonstrated in the Randall-Selitto, Von Frey, and hot plate tests. It restored monoaminergic balance and reduced the contents of glutamate and substance P. API suppressed aryl hydrocarbon receptors (AHR), kynurenine (KYN), indoleamine 2,3-dioxygenase (IDO), and nuclear factor kappa B (NF-κB) overexpression in the spinal cord. API hampered astrogliosis as evidenced by reduced GFAP immunohistochemical expression and its associated neuroinflammation and oxidative stress. Consequently, it inhibited A1 astrocytes polarization as evidenced by diminished their markers, namely C3, C1q, and S100β, contrary to upleveling S100A10, an A2 phenotype's marker. In conclusion, API mitigated FM-like pain symptoms by driving astrocyte polarization towards the neuroprotective A2 through modulating the KYN/AHR axis and its interaction with NF-κB signaling.