Expression of mdr isoforms in mice during estrous cycle and under hormone stimulation

Schiengold, Marion; Schwantes, Lavı́nia; Ribeiro, Maria Flávia Marques; Lothhammer, Nívia; Gonzalez, Tatiana Pereira; Nardi, Nance Beyer

doi:10.1590/s1415-47572006000400029

Cited by 5 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar sex differences in SE induction rate have previously been described in mice (Buckmaster and Haney, 2012) and rats (Mejı́as-Aponte et al, 2002), and are probably not based on sex differences in pharmacokinetics of pilocarpine (Omori et al, 2004). Rather, they may be attributed to sex-dependent sexual hormone levels occurring in the estrus cycle, which have been shown to influence expression levels of PGP (Schiengold et al, 2006). Indeed, evidence suggests that the degree of multidrug transporter-mediated efflux activity at the blood-brain barrier might be sex-related (Morris et al, 2003).…”

Section: Discussionsupporting

confidence: 71%

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

Römermann

Löscher

Bankstahl

2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

As a result of the growing availability of genetically engineered mouse lines, the pilocarpine post-status epilepticus (SE) model of temporal lobe epilepsy is increasingly used in mice. A discrepancy in pilocarpine sensitivity in FVB/N wild-type versus P-glycoprotein (PGP)-deficient mice precipitated the investigation of the interaction between pilocarpine and two major multidrug transporters at the blood-brain barrier. Doses of pilocarpine necessary for SE induction were determined in male and female wild-type and PGP-deficient mice. Brain and plasma concentrations were measured following low (30-50 mg×kg 21 i.p.) and/or high (200 mg×kg 21 i.p.) doses of pilocarpine in wild-type mice, and mice lacking PGP, breast cancer resistance protein (BCRP), or both transporters, as well as in rats with or without pretreatment with lithium chloride or tariquidar. Concentration equilibrium transport assays (CETA) were performed using cells overexpressing murine PGP or BCRP. Lower pilocarpine doses were necessary for SE induction in PGP-deficient mice. Brain-plasma ratios were higher in mice lacking PGP or PGP and BCRP, which was also observed after pretreatment with tariquidar in mice and in rats. Lithium chloride did not change brain penetration of pilocarpine. CETA confirmed transport of pilocarpine by PGP and BCRP. Pilocarpine is a substrate of PGP and BCRP at the rodent blood-brain barrier, which restricts its convulsive action. Future studies to reveal whether strain differences in pilocarpine sensitivity derive from differences in multidrug transporter expression levels are warranted.

show abstract

Section: Discussionsupporting

confidence: 71%

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

Römermann

Löscher

Bankstahl

2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…1) exhibit some similarities, with higher expression in early-to midluteal phases. This could suggest regulation by steroid hormones during the estrous cycle, as was reported for other ABC carriers such as MDR1 up-regulated by progesterone and repressed by estrogen in mouse endometrium (37). However, in the present study, we have concentrated on possible regulation by OT and IFN known to regulate PG biosynthesis and action at the time of recognition of pregnancy (5,10,38).…”

Section: Discussionmentioning

confidence: 61%

The Multidrug Resistance-Associated Protein 4 (MRP4) Appears as a Functional Carrier of Prostaglandins Regulated by Oxytocin in the Bovine Endometrium

et al. 2011

View full text Add to dashboard Cite

Prostaglandins (PG) are involved in several female reproductive processes, and their action is regulated at the levels of biosynthesis, catabolism, and signal transduction. Facilitated transport across cell membranes emerges as an additional checkpoint regulating PG action. We have already reported on the influx transporter solute carrier organic anion transporting polypeptide (SLCO2A1) [PG transporter (PGT)] in relation to PG action in the bovine endometrium. In the present study, we report on the functional expression and regulation of multidrug resistance-associated protein 4 (MRP4)/ATP-binding cassette carrier 4, an alternate PG transporter belonging to the ATP-binding cassette carrier (ABC) family. We have found that MRP4 protein was present throughout the estrous cycle and exhibited a pattern of expression similar to that of PGT with maximal expression during early-mid luteal phase in the bovine endometrium. Functional expression and regulation of MRP4 was studied in vitro using the newly developed bovine endometrial epithelial bEEL and stromal CSC cell lines. Oxytocin (OT) stimulated PGF2α production and MRP4 mRNA and protein in a time- and dose-dependent manner but had no effect on PGT. OT induced preferred accumulation of PG outside the cells and secretion toward the basolateral side of polarized bEEL cells grown on membrane inserts. MK-571 and indomethacin, two documented inhibitors of MRP4 activity, blocked preferred accumulation of PG, but interferon-τ and NS-398 had no effect on MRP4 expression or the direction of PG transport. Our results suggest that MRP4 is a functional PG carrier under the regulation of OT in the bovine endometrium.

show abstract

“…Verapamil, a common PGP substrate, showed lower brain uptake in female mice than male mice, suggesting higher PGP expression levels in female mice ( Dagenais et al., 2001 ). Because PGP expression levels are influenced by sexual hormone levels occurring during the oestrus cycle ( Schiengold et al., 2006 ), several studies have reported similar sex-related differences in SE development in both rats and mice ( Mejías-Aponte et al., 2002 ; Morris et al., 2003 ; Buckmaster and Haney, 2012 ). Several studies have implicated the excitatory neurotransmitter glutamate in the underlying mechanism that activates PGP ( Bauer et al., 2007 ; Zibell et al., 2009 ; Hartz et al., 2019 ; Soldner et al., 2019 ).…”

Section: The Limitations Strike Back: Imperfections In the Lithium-pimentioning

confidence: 99%

The evolution of the pilocarpine animal model of status epilepticus

Juvale

Has

2020

Heliyon

View full text Add to dashboard Cite

The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model of status epilepticus: a latency period followed by spontaneous recurrent seizures, replication of behavioural, electrographic, metabolic, and neuropathological changes, as well as, pharmacoresistance to anti-epileptic drugs similar to that observed in human status epilepticus. However, this model is also characterized by high mortality rates and studies in recent years have also seen difficulties in seizure induction due to pilocarpine resistant animals. This can be attributed to differences in rodent strains, species, gender, and the presence of the multi-transporter, P-glycoprotein at the blood brain barrier. The current paper highlights the various alterations made to the original pilocarpine model over the years to combat both the high mortality and low induction rates. These range from the initial lithium-pilocarpine model to the more recent Reduced Intensity Status Epilepticus (RISE) model, which finally brought the mortality rates down to 1%. These modifications are essential to improve animal welfare and future experimental outcomes.

show abstract

Expression of mdr isoforms in mice during estrous cycle and under hormone stimulation

Cited by 5 publications

References 34 publications

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

The Multidrug Resistance-Associated Protein 4 (MRP4) Appears as a Functional Carrier of Prostaglandins Regulated by Oxytocin in the Bovine Endometrium

The evolution of the pilocarpine animal model of status epilepticus

Contact Info

Product

Resources

About