ABSTRACT
Purpose: Modafinil is a vigilance-enhancing drug licensed for narcolepsy. The use of modafinil leads to various neuromodulatory effects with very low abuse potential. A body of evidence suggested that modafinil may have anti-parkinsonian effects. This study was designed to evaluate whether modafinil could improve motor dysfunction in the 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. Methods: Male Wistar rats (180-220 g, n= 98) were used in this study. Parkinsonism was induced by injection of 6-hydroxydopamine (10 µg/2µl in 0.2 % ascorbic acid-saline) into the right striatum. Parkinsonian rats received intraperitoneal (ip) injections of modafinil (50, 75, and 100 mg/kg) and catalepsy-like immobility was assessed by the bar test (BT). Furthermore, involvement of dopamine D1 and D2 receptors in modafinil's anti-parkinsonian effects was studied. For this purpose, parkinsonian animals were pretreated with SCH23390 and raclopride (the dopamine D1 and D2 receptor anatgonists, respectively) or SCH23390 + raclopride, and then assessed by the BT. Results: Modafinil (100 mg/kg) showed anti-cataleptic effects in the BT. Notably, the effect of modafinil in the BT was reversed in parkinsonian rats pretreated with raclopride (1.25 mg/kg) and/or SCH23390 + raclopride (0.75 and 1.25 mg/kg, respectively), but not in those pretreated with SCH23390 (0.75 mg/kg). Conclusion: Acute administration of modafinil improves 6-OHDA-induced motor impairment possibly through activation of dopamine D2 receptors.
ABSTRACT
AMPK is the key switch for providing the energy balance between cellular anabolic and catabolic processes. In this study, we aimed to screen the PRKAG1 (AMPKγ1) gene in high, moderate, and low producing Holstein dairy cows. A sample of 100 pregnant dairy cows, comprising 41 high, 33 moderate, and 26 low milk yields were selected from three large dairy herds in Isfahan province of Iran. Body condition score (BCS) was estimated before parturition while beta hydroxyl butyric acid (BHBA) as a measure of ketone bodies was measured at the fifth day postpartum. In addition, using three primer pairs covering exons 2-11 and 3'-UTR of the PRKAG1 gene, a random sample of 10 high milk yield dairy cows were amplified and sequenced. The sequencing results showed the presence of a T12571C mutation in intron 6 and a T14280C mutation in the 3'-untranslated region (UTR) of the PRKAG1 gene. Following a PCR reaction for amplification of the 3'-UTR amplicons, single strand conformation polymorphism (SSCP) assay was implemented for discrimination of the mutation in the studied population. Then, we evaluated if the mutation associates with the BCS, serum BHBA level, and production traits. The experimental analysis showed that the mutated allele significantly increased the BHBA level, BCS, as well as milk and protein yield. Bioinformatic study revealed that this 3'-UTR mutation distorts the target site of mir-423-5p microRNA which is one of the most highly expressed microRNAs in the bovine mammary gland, liver, and kidney. Given the role of AMPK in energy metabolism, the newly identified 3'-UTR mutation highlights the importance of AMPK and suggests a role of miRNAs for regulation of cellular metabolism, metabolism disorders, and production traits in Holstein dairy cows.
