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

Abstract

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.

Apigenin Attenuates Hippocampal Microglial Activation and Restores Cognitive Function in Methotrexate-Treated Rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway

“…We recorded a significant decline in BDNF levels downstream of CREB due to MTX injections. These results support the previous data reporting that decreased CREB/BDNF axis results in impaired neurogenesis and neuroinflammation as well as neuronal survival [16,48,54].…”

“…Furthermore, miR-15a downregulation, upstream of ROCK-1, was previously associated with AD [47]. Herein, miR-15a was dramatically downregulated in the hippocampus of MTX-treated rats, supporting the previous findings which correlated the downregulation of miR-15a with the overexpression of ROCK-1 [18,48]. ROCK-1 activation has been lately proven to have a role in mediating neuroinflammation via directly evoking microglial activation through increasing M1 neuroinflammatory phenotype size and count [49,50] or indirectly via the effect of ROCK-1 on ERK1/2/CREB/ BDNF pathway [51,52].…”

Dietary zinc protects against methotrexate-induced neurotoxicity in rats via modulation of oxidative stress, inflammation and neuronal energy metabolism

“…Methotrexate (MTX) is an antimetabolite used broadly in the management of cancers and also as an immunosuppressant in the managemet of rheumatoid arthritis [15]. It has been used alone or as an adjunct in the treatment of non-Hodgkin's lymphoma, acute lymphoblastic leukemia breast, uterine, gestational and lung cancers [16]. In the last decade, there has been increasing evidence of methotrexate-related neurotoxicity [3,[15][16][17][18].…”

“…It has been used alone or as an adjunct in the treatment of non-Hodgkin's lymphoma, acute lymphoblastic leukemia breast, uterine, gestational and lung cancers [16]. In the last decade, there has been increasing evidence of methotrexate-related neurotoxicity [3,[15][16][17][18]. While age is a very important factor in the development of methotrexate-induced neurotoxicity, the severity of the neurological deficits observed with MTX has also been linked to dose, route of administration, and combination [19,20].…”

“…In the last decade, there has been increasing evidence of methotrexate-related neurotoxicity [3,[15][16][17][18]. While age is a very important factor in the development of methotrexate-induced neurotoxicity, the severity of the neurological deficits observed with MTX has also been linked to dose, route of administration, and combination [19,20]. Methotrexate-related neurotoxicity manifests a leucoencephalopathy that presents clinically as transient ischemic attacks, convulsion, encephalopathy, dementia, movement disorders.…”