The Effect of Meclofenoxate on the Transcriptome of Aging Brain of Nothobranchius guentheri Annual Killifish

Abstract

Annual fish of the genus Nothobranchius are promising models for aging research. Nothobranchius reproduces typical aspects of vertebrate aging, including hallmarks of brain aging. Meclofenoxate (MF) is a well-known compound that can enhance cognitive performance. The drug is prescribed for asthenic conditions, trauma, and vascular diseases of the brain. It is believed that MF is able to delay age-dependent changes in the human brain. However, until now, there has been no study of the MF effect on the brain transcriptome. In the present work, we performed an RNA-Seq study of brain tissues from aged Nothobranchius guentheri, which were almost lifetime administered with MF, as well as young and aged control fish. As expected, in response to MF, we revealed significant overexpression of neuron-specific genes including genes involved in synaptic activity and plasticity, neurotransmitter secretion, and neuron projection. The effect was more pronounced in female fish. In this aspect, MF alleviated age-dependent decreased expression of genes involved in neuronal activity. In both treated and untreated animals, we observed strong aging-associated overexpression of immune and inflammatory response genes. MF treatment did not prevent this effect, and moreover, some of these genes tended to be slightly upregulated under MF treatment. Additionally, we noticed upregulation of some genes associated with aging and cellular senescence, including isoforms of putative vascular cell adhesion molecule 1 (VCAM1), protein O-GlcNAcase (OGA), protein kinase C alpha type (KPCA), prolow-density lipoprotein receptor-related protein 1 (LRP1). Noteworthy, MF treatment was also associated with the elevated transcription of transposons, which are highly abundant in the N. guentheri genome. In conclusion, MF compensates for the age-dependent downregulation of neuronal activity genes, but its effect on aging brain transcriptome still cannot be considered unambiguously positive.

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

“…Using genes that are differentially targeted by age as input to a web-based drug repurposing tool CLUEreg [36], we identified 150 small molecule drug candidates (Supplementary Material S2) with potential to reverse the aging-associated regulatory alterations in the gene regulatory networks from non-cancerous lung samples. Some of these drugs, henceforth referred to as “geroprotective drugs”, including Carnosol [37], Curcumin [38], Cucurbitacin B [39], Isonicotinamide [40], Meclofenoxate [41], Scriptaid [42], and Withaferin A [43] have already been shown to have potential geroprotective effects in various animal models, including humans. Among these 150 geroprotective drug candidates, we found several FDA-approved anti-cancer drugs, including Trametinib, Doxorubicin, Alisertib, Actinomycin-d, Toremifene, and Plumbagin, as well as several investigational drugs with potential anti-tumor effects including Avrainvillamide analogs [44], aurora kinase inhibitors (MK-5108, AT-9283) [45], Avicins [46], HMN-214 [47], Chaetocin [48], ron kinase inhibitors [49], and Linifanib [50], among others.…”

“…Isonicotinamide [40], Meclofenoxate [41], Scriptaid [42], and Withaferin A [43] have already been shown to have potential geroprotective effects in various animal models, including humans. Among these 150 geroprotective drug candidates, we found several FDA-approved anti-cancer drugs, including Trametinib, Doxorubicin, Alisertib, Actinomycin-d, Toremifene, and Plumbagin, as well as several investigational drugs with potential anti-tumor effects including Avrainvillamide analogs [44], aurora kinase inhibitors (MK-5108, AT-9283) [45] , Avicins [46], HMN-214 [47],…”

Nootropics as Cognitive Enhancers: Types, Dosage and Side Effects of Smart Drugs

“…The ability to alleviate memory deficits and neuronal damage may benefit cerebrovascular dementia [55]. The RNA-Seq study of brain tissues of Nothobranchius guentheri, which received meclofenoxate for almost a lifetime, concluded that while meclofenoxate compensated for age-dependent downregulation of neuronal activity genes, its effect on the aging brain transcriptome still could not be considered unequivocally positive [56].…”

“…Oral administration of meclofenoxate to rats (100 mg/kg, daily fo 37 days) significantly improved memory impairment, and reduced neuronal damage proinflammatory mediator levels, and oxidative stress to normal levels. The ability to al leviate memory deficits and neuronal damage may benefit cerebrovascular dementia [55] The RNA-Seq study of brain tissues of Nothobranchius guentheri, which received meclo fenoxate for almost a lifetime, concluded that while meclofenoxate compensated for age dependent downregulation of neuronal activity genes, its effect on the aging brain tran scriptome still could not be considered unequivocally positive [56].…”