Effects of Sertraline and Fluoxetine on P-Glycoprotein at Barrier Sites: In Vivo and In Vitro Approaches

Background and Purpose

Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.

Experimental Approach

The P-gp substrate, tritiated digoxin ([³H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.

Key Results

In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [³H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.

Conclusions and Implications

Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.     

Conservation Strategy for African Medicinal Species: <i>In Vitro</i> Biotechnological Approach

The use of medicinal plants for different therapeutic values is well documented in African continent. African diverse biodiversity hotspots provide a wide range of endemic species, which ensures a potential medicinal value. The feasible conservation approach and sustainable harvesting for the medicinal species remains a huge challenge. However, conservation approach through different biotechnological tools such as micropropagation, somatic embryogenesis, synthetic seed production, hairy root culture, molecular markers based study and cryopreservation of endemic African medicinal species is much crucial. In this review, an attempt has been made to provide different in vitro biotechnological approaches for the conservation of African medicinal species. The present review will be helpful in further technology development and deciding the priorities at decision-making levels for in vitro conservation and sustainable use of African medicinal species.     

Growth and alkaloid production along with expression profiles of biosynthetic pathway genes in two contrasting morphotypes of prickly and prickleless Solanum viarum Dunal

Protoplasma - Growth and production kinetics of three important glycoalkaloids viz. α-solanine, solanidine, and solasodine in two contrasting prickly and prickleless plants of Solanum viarum...     

An in silico analysis of deleterious single nucleotide polymorphisms and molecular dynamics simulation of disease linked mutations in genes responsible for neurodegenerative disorder

Abstract

Mutation in two genes deglycase gene (DJ-1) and retromer complex component gene (VPS35) are linked with neurodegenerative disorder such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. DJ-1 gene located at 1p36 chromosomal position and involved in PD pathogenesis through many pathways including mitochondrial dysfunction and oxidative injury. VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for basis of VPS35 related PD. The study focuses on identifying most deleterious SNPs through computational analysis. Result obtained from various bioinformatics tools shows that D149A is most deleterious in DJ-1 and A54W, R365H, and V717M are most deleterious in VPS35. To understand the functionality of protein comparative modeling of DJ-1 and VPS35 native and mutants was done by MODELLER. The generated structures are validated by two web servers–ProSa and RAMPAGE. Molecular dynamic simulation (MDS) analysis done for the most validated structures to know the functional and structural nature of native and mutants protein of DJ-1 and VPS35. Native structure of DJ-1 and VPS35 show more flexibility through MDS analysis. DJ-1 D149A mutant structures become more compact which shows the structural perturbation and loss of DJ-1 protein function which in turn are probable cause for PD. A54W, R365H, and V717M mutant protein of VPS35 also shows compactness which cause structure perturbation and absence of retromer function which likely to be linked to PD pathogenesis. This in silico study may provide a new insight for fundamental molecular mechanism involved in Parkinson’s disease.

Communicated by Ramaswamy H. Sarma     

IGFBP3 gene promoter methylation analysis and its association with clinicopathological characteristics of colorectal carcinoma

Molecular Biology Reports - Promoter methylation mediated silencing of tumor suppressor genes plays an important role in the tumorigenesis of colorectal carcinoma (CRC). Tumor suppressor gene,...     

Chemical activators: A novel and sustainable management approach for Meloidogyne incognita (Kofoid and White) Chitwood in Chamomilla recutita L

Use of chemical activator for the management of root-knot disease in medicinal and aromatic plants can become an attractive alternative to traditionally used nematicides. Large numbers of chemical molecules are present in the plants and are involved in the induction of different types of proteins. The purpose of our research study is to explore the possibilities of resistance factors that are inherent in the plant by treating them with few chemical activators to activate against root-knot nematode infection. Efforts were made to achieve a satisfactory suppression of root-knot nematode, Meloidogyne incognita, a serious menace to successful cultivation of chamomile, Matricaria recutita L. Rauch (syn. Matricaria chamomilla L. Fain. Asteraceae) causing root-knot disease through use of different chemical activators. Here we examined selected groups of resistance activator viz. Isonicotinamide, 2-chloronicotinic acid, 5-nitrosalicylic acid, 4-chlorosalicylic acid, DL-2 aminobutyric acid, 2-aminobutyric acid, O-acetylsalicylic acid, 4-amino salicylic acid, salicylic acid and these were used as soil drench using 3 week old seedlings transplanted to root-knot nematode infested pots. Maximum reduction in root-knot severity and nematode population occurred with 4-chlorosalicylic acid, O-acetyl salicylic acid, 2-chloronicotinic acid and gave significant flower yield advantages. Present experiment suggests a strong possibility of these activators in integrated management for protection against plant parasitic nematodes.     

Determination of biotic aetiology of tapping panel dryness (TPD) syndrome of rubber tree (Hevea brasiliensis) by return-polyacrylamide gel electrophoresis (R-PAGE) technique

Tapping panel dryness (TPD) syndrome affecting rubber tree (Hevea brasiliensis) is known to reduce natural latex production. Its aetiology remains ambiguous despite long years of research. A low molecular weight RNA similar to viroid RNA was isolated from TPD-affected samples of rubber trees. In the present study, a modified return-polyacrylamide gel electrophoresis procedure was standardised. The viroid-like low molecular weight (LMW) RNA was found associated with leaf, bark and root tissues and rubber seedlings. The technique was employed to detect LMW RNA in different clones of rubber planted in different locations and in bud-grafted plants. The LMW RNA isolated from TPD-affected trees was found infectious on seedlings of tomato cv Pusa Ruby. The LMW RNA was reisolated from symptomatic tomato leaves but not from control plants. This is for the first time that a biotic agent, a viroid RNA, is found consistently associated with the syndrome. The technology developed can be useful to demonstrate the onset of TPD in untapped trees in the absence of other methods such as nucleic acid hybridisation.     

Association of peroxisome proliferator activated receptor-γ gene with non-alcoholic fatty liver disease in Asian Indians residing in north India

Background

Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD.

Methods

In this case–control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction–restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed.

Results

Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist–hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p = 0.04), total cholesterol (p = 0.01), ALK (p = 0.04) and gamma-glutamyl transpeptidase (p = 0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1 = 0.1; p = 0.006) and controls (D1 = 0.07; p = 0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09–2.45, p = 0.05)].

Conclusion

Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD.