DL-Phenylalanine

Importance of dopaminergic neurotransmission for the RU 24969-induced locomotor activity of male and female rats during the preweanling period.[Pubmed:33205248]

Naunyn Schmiedebergs Arch Pharmacol. 2020 Nov 18. pii: 10.1007/s00210-020-02011-z.

There is disagreement about whether the locomotor activity produced by serotonin (5-HT) 1A/1B receptor agonists is ultimately mediated through a dopaminergic mechanism or is independent of dopamine (DA) system functioning. Using a developing rat model, we examined whether DA neurotransmission is necessary for the locomotor activity produced by 5-HT1A/1B receptor stimulation. Depending on experiment, male and female preweanling rats were pretreated with vehicle, the monoamine-depleting agent reserpine, the 5-HT synthesis inhibitor 4-chloro-DL-Phenylalanine methyl ester hydrochloride (PCPA), the DA synthesis inhibitor proportional, variant-methyl-DL-p-tyrosine (AMPT), or the D1 and D2 receptor antagonists SCH 23390 and raclopride, respectively. After completing the pretreatment regimen, the behavioral effects of saline and the 5-HT1A/1B receptor agonist RU 24969 were assessed during a 2-h test session. Locomotor activity in the center and margin of the testing chamber was recorded. RU 24969's locomotor activating effects were sensitive to blockade of the D2 receptor, but not the D1 receptor. The DA synthesis inhibitor (AMPT) significantly attenuated the RU 24969-induced locomotor activity of preweanling rats, as did the 5-HT synthesis inhibitor PCPA. The latter result suggests that presynaptic 5-HT1A/1B receptors may have a role in mediating RU 24969-induced locomotion during the preweanling period. DA neurotransmission, especially involving D2 receptors, is necessary for the 5-HT1A/1B-mediated locomotor activity of preweanling rats. The actions of PCPA, reserpine, and SCH 23390 differ substantially between preweanling and adult rats, suggesting that the neural mechanisms underlying these DA/5-HT interactions vary across ontogeny.

PLGA Membranes Functionalized with Gelatin through Biomimetic Mussel-Inspired Strategy.[Pubmed:33147761]

Nanomaterials (Basel). 2020 Nov 2;10(11). pii: nano10112184.

Electrospun membranes have been widely used as scaffolds for soft tissue engineering due to their extracellular matrix-like structure. A mussel-inspired coating approach based on 3,4-dihydroxy-DL-Phenylalanine (DOPA) polymerization was proposed to graft gelatin (G) onto poly(lactic-co-glycolic) acid (PLGA) electrospun membranes. PolyDOPA coating allowed grafting of gelatin to PLGA fibers without affecting their bulk characteristics, such as molecular weight and thermal properties. PLGA electrospun membranes were dipped in a DOPA solution (2 mg/mL, Tris/HCl 10 mM, pH 8.5) for 7 h and then incubated in G solution (2 mg/mL, Tris/HCl 10 mM, pH 8.5) for 16 h. PLGA fibers had an average diameter of 1.37 +/- 0.23 microm. Quartz crystal microbalance with dissipation technique (QCM-D) analysis was performed to monitor DOPA polymerization over time: after 7 h the amount of deposited polyDOPA was 71 ng/cm(2). After polyDOPA surface functionalization, which was, also revealed by Raman spectroscopy, PLGA membranes maintained their fibrous morphology, however the fiber size and junction number increased. Successful functionalization with G was demonstrated by FTIR-ATR spectra, which showed the presence of G adsorption bands at 1653 cm(-1) (Amide I) and 1544 cm(-1) (Amide II) after G grafting, and by the Kaiser Test, which revealed a higher amount of amino groups for G functionalized membranes. Finally, the biocompatibility of the developed substrates and their ability to induce cell growth was assessed using Neonatal Normal Human Dermal Fibroblasts.

Transient serotonin depletion at adolescence, but not at early infancy, reduced subsequent anxiety-like behavior and alcohol intake in female mice.[Pubmed:33011817]

Psychopharmacology (Berl). 2020 Oct 4. pii: 10.1007/s00213-020-05670-1.

RATIONALE: Serotonin (5-HT) plays an important role in the organization of the central nervous system and in the development of social interaction deficits and psychiatric disorders, including anxiety, depression, and addiction disorders. Notably, disruption of the 5-HT system during sensitive periods of development exerts long-term consequences, including altered anxiety response and problematic use of alcohol. OBJECTIVE: we analyzed, in mice, the effects of transient 5-HT depletion at infancy or adolescence on subsequent anxiety-like behavior and alcohol intake during adolescence. METHODS: C57/BL6 male and female mice were administered a 5-HT synthesis inhibitor (PCPA; 4-chloro-DL-Phenylalanine methyl ester hydrochloride) at infancy (postnatal days 14-16 [PD14-16]) or adolescence (PD40-42). Eleven (+/- 1) days after treatment, mice were assessed for ethanol intake in daily two-bottle choice tests and for anxiety response via the elevated plus maze. RESULTS: Female, but not male, mice transiently depleted of 5-HT at adolescence (but not those depleted at the perinatal stage) exhibited a significant reduction in anxiety response, which was accompanied by a significant reduction on alcohol intake. CONCLUSION: Transient 5-HT inhibition at adolescence may act, in females, as a protective factor for the emergence of anxiety disorders and problematic use of alcohol during adolescence.

Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats.[Pubmed:32750446]

Neuropharmacology. 2020 Nov 1;178:108238.

Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT3-R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-DL-Phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies.

Obtainment, selection and characterization of a mutant strain of Kluyveromyces marxianus that displays improved production of 2-phenylethanol and enhanced DAHP synthase activity.[Pubmed:32706912]

J Appl Microbiol. 2020 Jul 24.

AIMS: Yeasts produce 2-phenylethanol (2-PE) from sugars via de novo synthesis; however, its synthesis is limited due to feedback inhibition on the isofunctional 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP) synthases (Aro3p and Aro4p). This work aimed to select Kluyveromyces marxianus mutant strains with improved capacity to produce 2-PE from sugars. METHODS AND RESULTS: Kluyveromyces marxianus CCT 7735 mutant strains were selected from UV irradiation coupled with screening of p-fluoro-DL-Phenylalanine (PFP) tolerant strains on culture medium without l-Phe addition. Most of them produced 2-PE titres higher than the parental strain and the Km_PFP41 mutant strain stood out for displaying the highest 2-PE specific production rate. Moreover it showed higher activity of DAHP synthase than the parental strain. We sequenced both ARO3 and ARO4 genes of Km_PFP41 mutant and identified mutations in ARO4 which caused changes in both size and conformation of the Aro4p. These changes seem to be associated with the enhanced activity of DAHP synthase and improved production of 2-PE exhibited by that mutant strain. CONCLUSIONS: The Km_PFP41 mutant strain presented improved 2-PE production via de novo synthesis and enhanced DAHP synthase activity. SIGNIFICANCE AND IMPACT OF THE STUDY: The mutant strain obtained in this work may be exploited as a yeast cell factory for high-level synthesis of 2-PE.

MK801-induced locomotor activity in preweanling and adolescent male and female rats: role of the dopamine and serotonin systems.[Pubmed:32445054]

Psychopharmacology (Berl). 2020 Aug;237(8):2469-2483.

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor proportional, variant-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-Phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.

Effects of Thryptophan Hydroxylase Blockade by P-Chlorophenylalanine on Contextual Memory Reconsolidation after Training of Different Intensity.[Pubmed:32197439]

Int J Mol Sci. 2020 Mar 18;21(6). pii: ijms21062087.

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval induces the plasticity, which may result in reconsolidation of the original memory and needs critical molecular events to stabilize the memory or its extinction. 4-Chloro-DL-Phenylalanine (P-chlorophenylalanine-PCPA) depresses the most limiting enzyme of serotonin synthesis the tryptophan hydroxylase. It is known that PCPA reduces the serotonin content in the brain up to 10 times in rats (see Methods). We hypothesized that the PCPA could behave the similar way in snails and could reduce the content of serotonin in snails. Therefore, we investigated the effect of PCPA injection on contextual memory reconsolidation using a protein synthesis blocker in snails after training according to two protocols of different intensities. The results obtained in training according to the first protocol using five electrical stimuli per day for 5 days showed that reminding the training environment against the background of injection of PCPA led to a significant decrease in contextual memory. At the same time, the results obtained in training according to the second protocol using three electrical stimuli per day for 5 days showed that reminding the training environment against the injection of PCPA did not result in a significant change in contextual memory. The obtain results allowed us to conclude that the mechanisms of processes developed during the reconsolidation of contextual memory after a reminding depend both on the intensity of learning and on the state of the serotonergic system.

Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.[Pubmed:31655095]

Behav Brain Res. 2020 Feb 3;379:112302.

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor proportional, variant-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-Phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.

Chiral Analysis of Non-Protein Amino Acids by Capillary Electrophoresis.[Pubmed:31347125]

Methods Mol Biol. 2019;2030:277-291.

A high number of non-protein amino acids are chiral compounds that have demonstrated to be relevant in different fields. Their determination enables to obtain valuable information related to food quality and safety and has also a high interest from a biological point of view since many of them are key compounds in metabolic pathways or are related with different pathologies.In the development of analytical methodologies to perform chiral separations, capillary electrophoresis (CE) is well-established and one of the most powerful separation techniques as a consequence of its high efficiency, short analysis time, and versatility.This chapter shows, by means of three interesting examples, the application of different CE methodologies to the chiral analysis of non-protein amino acids. The first example describes different electrokinetic chromatography (EKC)-UV methodologies based on the use of negatively charged cyclodextrins as chiral selectors to carry out the stereoselective separation of ten different non-protein amino acids of relevance from a biological or food analysis point of view. The second method illustrates the EKC-UV analysis of L-citrulline and its enantiomeric impurity in food supplements using sulfated-gamma-cyclodextrin as chiral selector. The last example shows the simultaneous enantiomeric separation of 3,4-dihydroxy-DL-Phenylalanine and all the other chiral constituents involved in the phenylalanine-tyrosine metabolic pathway by using an EKC-MS methodology.

Sedative and hypnotic effects of Vaccinium bracteatum Thunb. through the regulation of serotonegic and GABAA-ergic systems: Involvement of 5-HT1A receptor agonistic activity.[Pubmed:30551479]

Biomed Pharmacother. 2019 Jan;109:2218-2227.

The present study was conducted to investigate the sedative and hypnotic activities of Vaccinium bracteatum Thunb. fruit (VBFW) in an animal model and to identify the underlying mechanisms of its action. VBFW exhibited sedative effects through a reduction in the locomotor activity in the open field test (OFT). In addition, VBFW significantly reduced the sleep latency and increased total sleep duration in pentobarbital-induced sleeping behaviors in mice. The effects of 4-Chloro-DL-Phenylalanine methyl ester hydrochloride (PCPA) were studied in normal and serotonin-depleted mice. Additionally, the changes in the related serum corticosterone (CORT) and neurotransmitter levels were evaluated. Pretreatment with VBFW (50, and 100 mg/kg) produced a significant decrease in the immobility time in the forced swim test (FST), while VBFW 100 plus PCPA treatment attenuated the change in immobility time observed following administration of VBFW alone. However, VBFW plus PCPA treatments did not significantly influence the changes in the locomotor activity that were induced by VBFW alone. The results suggest that VBFW leads to a decrease in the levels of serum CORT and norepinephrine in the hippocampus (HC) region (P < 0.01). Furthermore, PCPA treatment alone decreased serotonin (5-HT) levels in the HC (P < 0.05) and the prefrontal cortex (PFC; P < 0.05), while VBFW plus PCPA significantly increased the 5-HT levels in both the HC and the PFC (P < 0.05). In addition, we also found that VBFW showed a strong agonistic effect at the 5-HT1A receptor by activating 5-HT1A receptor-mediated intracellular Ca(2+) and ERK1/2 phosphorylation. Similarly, VBFW (30 and 100 mug/mL) significantly increased the intracellular Cl(-) influx through its effects on the gamma-aminobutyric acid type A receptor (GABAA receptor) subunits (alpha5, beta1, and beta2) in primary rat cerebellar granule cells. Moreover, the glutamate decarboxylase (GAD)65/67 protein was upregulated following VBFW treatment (30 and 100 mug/mL). The results of our study indicate that VBFW induces sedative and hypnotic effects by regulating the serotonergic and GABAA-ergic systems, which is possibly associated with 5-HT1A receptor agonistic activity. Additionally, this data suggests that VBFW up-regulates intracellular Cl(-) and GABAA receptor subunits as well as GAD65/67 protein levels.

Anti-lung Cancer and Anti-angiogenic Activities of New Designed Boronated Phenylalanine Metal Complexes.[Pubmed:30051790]

Curr Drug Deliv. 2018;15(10):1417-1425.

BACKGROUND: Drug design and discovery studies still remain of great importance in the search for more convenient chemotherapeutic to avoid the drug resistance, systemic toxicity or the longterm side effects. OBJECTIVE: A series of mononuclear gold (III) and platinum (II) complexes based on 4-dihydroxyboryl- DL-Phenylalanine (BPA) was designed and synthesized, for the first time, by using 2, 2'-dipyridyl (L1) and 4, 4'-diaminobibenzyl (L2) ligands. Characterization of the synthesized complexes was achieved by using 1H-NMR, IR, MS and elemental analyses. METHOD: MTT cell viability, endothelial tube formation, cancer cell colony formation and TRITCphalloidin cytoskeleton staining assays were performed on human umbilical vein endothelial (HUVEC) and human lung adenocarcinoma (A549) cells to establish the anticancer and anti-angiogenic activities of the complexes. It was determined that the organometallic complexes that include 2, 2'-dipyridyl ligand have higher antiproliferative activity than L2-based complexes in the micromolar range. Colony formation experiments showed that the anchorage-independent growth ability of A549s was significantly affected by the complexes in a concentration-dependent manner though L1-based complexes were more effective than L2-based ones. RESULTS: It was also clearly observed that the complexes have significant anti-angiogenic and cytoskeleton alterative activities. Consequently, the phenylalanine-based organometallic complexes seem to have anti-lung cancer and anti-angiogenic activities depending on the ligand type and a great potential in oncology drug development because phenylalanine amino acid has an ability to cross the cell membrane by using L-amino acid transport system. CONCLUSION: Design, synthesis and activity studies with amino acid analogs should be therefore increased to discover more efficient drugs to cure cancer diseases.

Gut-derived serotonin contributes to bone deficits in colitis.[Pubmed:30030171]

Pharmacol Res. 2019 Feb;140:75-84.

Osteoporosis and bone fractures occur at higher frequency in patients with inflammatory bowel disease (IBD), and decreased bone mass is observed in animal models of colitis. Another consistent feature of colitis is increased serotonin (5-HT) availability in the intestinal mucosa. Since gut-derived 5-HT can decrease bone mass, via activation of 5-HT1B receptors on pre-osteoblasts, we tested the hypothesis that 5-HT contributes to bone loss in colitis. Colitis was chronically induced in mice by adding dextran sodium sulfate (DSS) to their drinking water for 21 days. At day 21, circulating 5-HT levels were elevated in DSS-inflamed mice. Micro-computed tomography of femurs showed a decrease in trabecular bone volume fraction, formation, and surface area, due largely to decreased trabecular numbers in DSS-treated mice. The colitis-induced loss of trabecular bone was significantly suppressed in mice treated with the 5-HT synthesis inhibitor, p-chloro-DL-Phenylalanine (PCPA; 300 mg/kg/day IP daily), and in mice treated with the 5-HT1B receptor antagonist GR55562 (1 mg/Kg/day SC daily). The 5-HT reuptake transporter (SERT) is critical for moving 5-HT from the interstitial space into enterocytes and from serum into platelets. Mice lacking SERT exhibited significant deficits in trabecular bone mass that are similar to those observed in DSS-inflamed mice, and these deficits were not extensively worsened by DSS-induced colitis in the SERT-/- mice. Taken together, findings from both the DSS and SERT-/- mouse models support a contributing role for 5-HT as a significant factor in bone loss induced by colitis.

Novel Intrapolymerization Doped Manganese-Eumelanin Coordination Nanocomposites with Ultrahigh Relaxivity and Their Application in Tumor Theranostics.[Pubmed:30027037]

Adv Sci (Weinh). 2018 Mar 25;5(7):1800032.

While magnetic resonance imaging contrast agents have potential in noninvasive image-guided tumor treatment, further developments are needed to increase contrast, biodegradability, and safety. Here, novel engineered manganese-eumelanin coordination nanocomposites (MnEMNPs) are developed via a facile one-pot intrapolymerization doping (IPD) approach in aqueous solution, through simple chemical oxidation-polymerization of the 3,4-dihydroxy-DL-Phenylalanine precursor with potassium permanganate serving as the Mn source and an oxidant. The resulting MnEMNPs possess ultrahigh longitudinal relaxivity (r1 value up to 60.8 mM(-1) s(-1) at 1.5 T) attributed to the high manganese doping efficiency (>10%) and geometrically confined conformation. Due to their high manganese chelation stability, excellent biocompatibility, and strong near-infrared absorption, high-performance longitudinal-transverse (T1-T2) dual-modal magnetic resonance/photoacoustic imaging and photothermal tumor ablation are achieved. Furthermore, the hydrogen peroxide-triggered decomposition behavior of MnEMNPs circumvents the poor biodegradation issue of many nanomaterials. This facile, convenient, economical, and efficient IPD strategy will open up new avenues for the development of high-performance multifunctional theranostic nanoplatforms in bionanomedicine.

S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression.[Pubmed:29379439]

Front Pharmacol. 2018 Jan 15;8:978.

Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-Phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to approximately 6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

PCPA protects against monocrotaline-induced pulmonary arterial remodeling in rats: potential roles of connective tissue growth factor.[Pubmed:29340081]

Oncotarget. 2017 Dec 4;8(67):111642-111655.

The purpose of this study was to investigate the mechanism of monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and determine whether 4-chloro-DL-Phenylalanine (PCPA) could inhibit pulmonary arterial remodeling associated with connective tissue growth factor (CTGF) expression and downstream signal pathway. MCT was administered to forty Sprague Dawley rats to establish the PAH model. PCPA was administered at doses of 50 and 100 mg/kg once daily for 3 weeks via intraperitoneal injection. On day 22, the pulmonary arterial pressure (PAP), right ventricle hypertrophy index (RVI) and pulmonary artery morphology were assessed and the serotonin receptor-1B (SR-1B), CTGF, p-ERK/ERK were measured by western blot or immunohistochemistry. The concentration of serotonin in plasma was checked by ELISA. Apoptosis and apoptosis-related indexes were detected by TUNEL and western blot. In the MCT-induced PAH models, the PAP, RVI, pulmonary vascular remodeling, SR-1B index, CTGF index, anti-apoptotic factors bcl-xl and bcl-2, serotonin concentration in plasma were all increased and the pro-apoptotic factor caspase-3 was reduced. PCPA significantly ameliorated pulmonary arterial remodeling induced by MCT, and this action was associated with accelerated apoptosis and down-regulation of CTGF, SR-1B and p-ERK/ERK. The present study suggests that PCPA protects against the pathogenesis of PAH by suppressing remodeling and inducing apoptosis, which are likely associated with CTGF and downstream ERK signaling pathway in rats.