Dexmedetomidine Alleviates Inflammatory Response and Oxidative Stress Injury of Vascular Smooth Muscle Cell via α2AR/PI3K/AKT Pathway in Intracranial Aneurysm

Zhang, Ze; Mu, Xiue; Zhou, Xiaohui

doi:10.21203/rs.3.rs-1240394/v1

Cited by 1 publication

(1 citation statement)

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“…On the other hand, Dex co-treatment elevated the BDNF expression and reversed the MTX-induced oxidative stress, as evidenced by the escalated SOD, and decreased MDA levels in the Dex co-treated group when compared to the MTX-treated rats. Similarly, previous studies have reported that Dex is able to alleviate oxidative stress injury in the vascular smooth muscle and lungs [54][55][56]. Together, our results reveal that Dex administration reduces the neurotoxic effect of MTX via upregulating BDNF expression and reducing oxidative stress in rats' hippocampus.…”

Section: Discussionsupporting

confidence: 88%

Dexmedetomidine Attenuates Methotrexate-Induced Neurotoxicity and Memory Deficits in Rats through Improving Hippocampal Neurogenesis: The Role of miR-15a/ROCK-1/ERK1/2/CREB/BDNF Pathway Modulation

Taha

Eldemerdash

Elshaffei

et al. 2023

IJMS

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Methotrexate (MTX) is a widely used neurotoxic drug with broad antineoplastic and immunosuppressant spectra. However, the exact molecular mechanisms by which MTX inhibits hippocampal neurogenesis are yet unclear. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has recently shown neuroprotective effects; however, its full mechanism is unexplored. This study investigated the potential of Dex to mitigate MTX-induced neurotoxicity and memory impairment in rats and the possible role of the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Notably, no former studies have linked this pathway to MTX-induced neurotoxicity. Male Sprague Dawley rats were placed into four groups. Group 1 received saline i.p. daily and i.v. on days 8 and 15. Group 2 received Dex at 10 μg/kg/day i.p. for 30 days. Group 3 received MTX at 75 mg/kg i.v. on days 8 and 15, followed by four i.p. doses of leucovorin at 6 mg/kg after 18 h and 3 mg/kg after 26, 42, and 50 h. Group 4 received MTX and leucovorin as in group 3 and Dex daily dosages as in group 2. Bioinformatic analysis identified the association of miR-15a with ROCK-1/ERK1/2/CREB/BDNF and neurogenesis. MTX lowered hippocampal doublecortin and Ki-67, two markers of neurogenesis. This was associated with the downregulation of miR-15a, upregulation of its target ROCK-1, and reduction in the downstream ERK1/2/CREB/BDNF pathway, along with disturbed hippocampal redox state. Novel object recognition and Morris water maze tests demonstrated the MTX-induced memory deficiencies. Dex co-treatment reversed the MTX-induced behavioral, biochemical, and histological alterations in the rats. These neuroprotective actions could be partly mediated through modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway, which enhances hippocampal neurogenesis.

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Section: Discussionsupporting

confidence: 88%