Neuroprotective effect of 3,3′-diindolylmethane and ɑ-naphthoflavone, aryl hydrocarbon receptor modulators in an experimental model of ischemic stroke

Abstract

Background: The aryl hydrocarbon receptor (AhR) mediated signaling pathway is being emerged as a current target for neuromodulation. The present study was conducted to characterize the neuroprotective action of AhR modulators, i.e., 3,3′-diindolylmethane (DIM) and ɑ-naphthoflavone (ANF) in an experimental model of stroke using transient middle cerebral artery occlusion (MCAO) in Wistar rats. Methods: The animals were treated with respective AhR modulators via intraperitoneal (i.p) injection 3 hrs after MCAO for 4 days (at 24 h interval). Following transient MCAO, the brain infarct volume, ND scoring, and various neuro behavioural tests were conducted to confirm the ischemic stroke. Further, oxidative stress parameters, inflammatory cytokines, and apoptotic mRNA expression were assessed. The histopathological changes in the brain of the rats were assessed using H&E staining and the results obtained were correlated with the molecular parameters. Results: Treatment with AhR modulators had significantly decreased the brain infarct volume, ND scoring and improved neuro-behivoral deficits in animals following MCAO. A significant decrease was also observed in the oxidative stress, pro-inflammatory cytokines, and apoptotic mRNA expression in the AhR ligand treated groups. Moreover, a significant improvement was observed in the neuronal damage following MCAO in the treatment groups. Conclusion: AhR pathway modulation may be taken as a valuable therapeutic target for treating acute ischemic stroke (AIS).

Laquinimod Inhibits Microglial Activation, Astrogliosis, BBB Damage, and Infarction and Improves Neurological Damage after Ischemic Stroke

“…Recently, AhR modulators, such as 3,3′diindolylmethane (DIM) and α-naphthoflavone (ANF), displays a significant neuroprotective effect in the ischemic stroke model. 28 Taken together, we suppose that LAQ also plays a part in ischemic stroke-induced neuronal damage, via regulating the activation of microglia and astrocyte. Until now, little is known about its effects on ischemic stroke.…”

“…LAQ, as an AhR receptor, has been used as a substitute for Fingomod in the treatment of MS. Recently, AhR modulators, such as 3,3′-diindolylmethane (DIM) and α-naphthoflavone (ANF), displays a significant neuroprotective effect in the ischemic stroke model . Taken together, we suppose that LAQ also plays a part in ischemic stroke-induced neuronal damage, via regulating the activation of microglia and astrocyte.…”

Current understanding and future directions of cruciferous vegetables and their phytochemicals to combat neurological diseases

“…Ramakrishna et al found that significant amounts of DIM are produced and were identified in highly perfused organs after I3C oral delivery (Ramakrishna, Jain, & Krishnamurthy, 2022) and, similar to I3C, DIM exhibited neuroprotection against MCAO I/R injury by ameliorating platelet aggregation and thrombosis (Ramakrishna et al, 2022b). This effect was achieved through AHR activation, antioxidant, and anti‐inflammatory mechanisms (Dhir et al, 2022) emphasizing that DIM regulates the pharmacological activities of I3C. DIM shows inhibitory effects on ischemia‐induced apoptosis and autophagy by decreasing AHR/CYPIAL signaling and increasing histone deacetylase activity (HDAC) activity in hippocampal neurons in adult rats (Rzemieniec et al, 2019).…”