Pharmaceuticals

722 KiB

Open AccessArticle

Endogenous Cannabinoid Production in the Rat Female Reproductive Tract Is Regulated by Changes in the Hormonal Milieu

by Heather B. Bradshaw and Cassandra Allard

Pharmaceuticals 2011, 4(6), 933-949; https://doi.org/10.3390/ph4060933 - 23 Jun 2011

Cited by 9 | Viewed by 10173

The endogenous cannabinoid (eCB) system is emerging as an important component of female reproductive tract physiology. The eCBs anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and N-arachidonoyl glycine (NAGly) were measured in the rat reproductive tract at five time points in the four-day estrous [...] Read more.

The endogenous cannabinoid (eCB) system is emerging as an important component of female reproductive tract physiology. The eCBs anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and N-arachidonoyl glycine (NAGly) were measured in the rat reproductive tract at five time points in the four-day estrous cycle, in acyclic retired breeders (RB), after ovariectomy (OVX), OVX + estrogen (E2), OVX + progesterone (P4), or OVX with E2+P4. eCBs were measured in the uterus, uterine adipose, ovaries, and ovarian adipose using HPLC/MS/MS. Levels of AEA, 2-AG, and NAGly were highest in the estrus phase of the estrous cycle in the uterus, whereas, only NAGly had differences in production in the ovaries across the cycle. All eCBs were lower in RB ovaries; however, the production of eCBs in the uterus of RB and OVX groups was more varied with NAGly showing the lowest levels of production in these groups. Levels of AEA in uterine fat were significantly higher or equivalent to levels in the uterus. However, levels of 2-AG and NAGly were dramatically lower in uterine fat verses the organ. Ovarian fat had significantly lower levels of all three eCBs. These data provide evidence that the hormonal milieu plays a significant and complex role in the production of eCBs in the female rat reproductive tract. Full article

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95 KiB

Open AccessReview

Cocaine and MDMA Induce Cellular and Molecular Changes in Adult Neurogenic Systems: Functional Implications

by Vivian Capilla-Gonzalez and Vicente Hernandez-Rabaza

Pharmaceuticals 2011, 4(6), 915-932; https://doi.org/10.3390/ph4060915 - 17 Jun 2011

Cited by 4 | Viewed by 7240

Abstract

The capacity of the brain to generate new adult neurons is a recent discovery that challenges the old theory of an immutable adult brain. A new and fascinating field of research now focuses on this regenerative process. The two brain systems that constantly [...] Read more.

The capacity of the brain to generate new adult neurons is a recent discovery that challenges the old theory of an immutable adult brain. A new and fascinating field of research now focuses on this regenerative process. The two brain systems that constantly produce new adult neurons, known as the adult neurogenic systems, are the dentate gyrus (DG) of the hippocampus and the lateral ventricules/olfactory bulb system. Both systems are involved in memory and learning processes. Different drugs of abuse, such as cocaine and MDMA, have been shown to produce cellular and molecular changes that affect adult neurogenesis. This review summarizes the effects that these drugs have on the adult neurogenic systems. The functional relevance of adult neurogenesis is obscured by the functions of the systems that integrate adult neurons. Therefore, we explore the effects that cocaine and MDMA produce not only on adult neurogenesis, but also on the DG and olfactory bulbs. Finally, we discuss the possible role of new adult neurons in cocaine- and MDMA-induced impairments. We conclude that, although harmful drug effects are produced at multiple physiological and anatomical levels, the specific consequences of reduced hippocampus neurogenesis are unclear and require further exploration. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

502 KiB

Open AccessReview

A Role for Sigma Receptors in Stimulant Self Administration and Addiction

by Jonathan L. Katz, Tsung-Ping Su, Takato Hiranita, Teruo Hayashi, Gianluigi Tanda, Theresa Kopajtic and Shang-Yi Tsai

Pharmaceuticals 2011, 4(6), 880-914; https://doi.org/10.3390/ph4060880 - 17 Jun 2011

Cited by 53 | Viewed by 10657

Abstract

Sigma₁ receptors (σ₁Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ₁Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, [...] Read more.

Sigma₁ receptors (σ₁Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ₁Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ₂R antagonist but not by a preferential σ₁R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

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370 KiB

Open AccessReview

Regeneration of Hair Cells: Making Sense of All the Noise

by Benjamin Kopecky and Bernd Fritzsch

Pharmaceuticals 2011, 4(6), 848-879; https://doi.org/10.3390/ph4060848 - 17 Jun 2011

Cited by 23 | Viewed by 10609

Abstract

Hearing loss affects hundreds of millions of people worldwide by dampening or cutting off their auditory connection to the world. Current treatments for sensorineural hearing loss (SNHL) with cochlear implants are not perfect, leaving regenerative medicine as the logical avenue to a perfect [...] Read more.

Hearing loss affects hundreds of millions of people worldwide by dampening or cutting off their auditory connection to the world. Current treatments for sensorineural hearing loss (SNHL) with cochlear implants are not perfect, leaving regenerative medicine as the logical avenue to a perfect cure. Multiple routes to regeneration of damaged hair cells have been proposed and are actively pursued. Each route not only requires a keen understanding of the molecular basis of ear development but also faces the practical limitations of stem cell regulation in the delicate inner ear where topology of cell distribution is essential. Improvements in our molecular understanding of the minimal essential genes necessary for hair cell formation and recent advances in stem cell manipulation, such as seen with inducible pluripotent stem cells (iPSCs) and epidermal neural crest stem cells (EPI-NCSCs), have opened new possibilities to advance research in translational stem cell therapies for individuals with hearing loss. Despite this, more detailed network maps of gene expression are needed, including an appreciation for the roles of microRNAs (miRs), key regulators of transcriptional gene networks. To harness the true potential of stem cells for hair cell regeneration, basic science and clinical medicine must work together to expedite the transition from bench to bedside by elucidating the full mechanisms of inner ear hair cell development, including a focus on the role of miRs, and adapting this knowledge safely and efficiently to stem cell technologies. Full article

(This article belongs to the Special Issue Stem Cell Therapy)

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Graphical abstract

658 KiB

Open AccessReview

Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

by David Pubill, Sara Garcia-Ratés, Jordi Camarasa and Elena Escubedo

Pharmaceuticals 2011, 4(6), 822-847; https://doi.org/10.3390/ph4060822 - 15 Jun 2011

Cited by 4 | Viewed by 11780

Abstract

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. [...] Read more.

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower K_i values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

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137 KiB

Open AccessReview

Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

by Luyi Zhou, Wei-Lun Sun and Ronald E. See

Pharmaceuticals 2011, 4(6), 804-821; https://doi.org/10.3390/ph4060804 - 14 Jun 2011

Cited by 10 | Viewed by 11394

Abstract

Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating [...] Read more.

Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

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Open AccessArticle

Use of Intravenous Amiodarone in the Treatment of Nifekalant-Resistant Arrhythmia: A Review of 11 Consecutive Cases with Severe Heart Failure

by Koji Nakagawa, Kazufumi Nakamura, Kengo Fukushima Kusano, Satoshi Nagase, Takeshi Tada, Masato Murakami, Yoshiki Hata, Hiroshi Morita, Kunihisa Kohno, Kazumasa Hina, Tohru Ujihira, Tohru Ohe and Hiroshi Ito

Pharmaceuticals 2011, 4(6), 794-803; https://doi.org/10.3390/ph4060794 - 31 May 2011

Cited by 2 | Viewed by 6722

Abstract

Background: Both nifekalant hydrochloride (NIF), a selective I_Kr blocker, and intravenous amiodarone (AMD), a multi-channel (including I_Kr blocking) blocker, have been reported to be efficacious for refractory arrhythmias. However, the optimal use of those antiarrhythmic drugs for refractory arrhythmia with [...] Read more.

Background: Both nifekalant hydrochloride (NIF), a selective I_Kr blocker, and intravenous amiodarone (AMD), a multi-channel (including I_Kr blocking) blocker, have been reported to be efficacious for refractory arrhythmias. However, the optimal use of those antiarrhythmic drugs for refractory arrhythmia with severe heart failure has not been established. Intravenous AMD might be effective for arrhythmias refractory to NIF in patients with severe heart failure. Here, we report that intravenous amiodarone was effective in the treatment of nifekalant-resistant in a group of arrhythmia patients with severe heart failure. Methods: Eleven severe heart failure patients who had received intravenous AMD for treatment of NIF-resistant arrhythmias were included in this study, and retrospective analysis was performed. Clinical efficacy (terminative and preventive effects on arrhythmia) of intravenous AMD was evaluated. Results: All cases were emergent cases and had depressed left ventricular ejection fraction (30 ± 13%). Clinical arrhythmias were ventricular fibrillation (VF) in four patients, ventricular tachycardia (VT) in six patients, and atrial fibrillation (AF) in one patient. NIF was administered to all patients by intravenous injection. After administration of NIF, VT/VF/AF was terminated in seven of the 10 patients, but a preventive effect was not obtained in any of the patients (NIF-resistance). Intravenous AMD (maintenance dose: 484 ± 166 mg/day) was effective both in termination (80%) and in prevention (80%) of VT/VF events in those patients. It was also effective in termination (80%) and prevention (60%) of AF events refractory to NIF. During continuous AMD administration, no significant adverse effects or proarrhythmic effects were observed in any of the patients. Five patients died within one month, but there was no arrhythmic deaths. Conclusions: Intravenous AMD was effective in NIF-resistant lethal arrhythmias and was relatively safe in emergent cases with severe heart failure. Full article

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369 KiB

Open AccessArticle

Mutual Balance between Vasohibin-1 and Soluble VEGFR-1 in Endothelial Cells

by Hiroki Miyashita, Hirotada Suzuki, Akihide Ohkuchi and Yasufumi Sato

Pharmaceuticals 2011, 4(6), 782-793; https://doi.org/10.3390/ph4060782 - 31 May 2011

Cited by 9 | Viewed by 6582

Abstract

Vasohibin-1 (VASH1) is a VEGF-inducible gene of endothelial cells (ECs) that acts as a negative feedback regulator of angiogenesis. To further characterize the function of VASH1, we transfected human VASH1 gene into the mouse EC line MS1, established stable VASH1 expressing clones, and [...] Read more.

Vasohibin-1 (VASH1) is a VEGF-inducible gene of endothelial cells (ECs) that acts as a negative feedback regulator of angiogenesis. To further characterize the function of VASH1, we transfected human VASH1 gene into the mouse EC line MS1, established stable VASH1 expressing clones, and determined gene alteration by cDNA microarray analysis. Among the various angiogenesis-related genes, vascular endothelial growth factor type 1 receptor (VEGFR-1) and its alternative spliced form, soluble VEGFR1 (sVEGFR-1), were found to be the most significantly down-regulated genes. Transient overexpression of VASH1 in human umbilical vein endothelial cells confirmed the down-regulation of VEGFR-1 and sVEGFR-1. sVEGFR-1 is a decoy receptor for VEGF and inhibits angiogenesis. Interestingly, when sVEGFR-1 was overexpressed in ECs, it inhibited the expression of VASH1 in turn. These results suggest that VASH1 and sVEGFR-1, two angiogenesis inhibitors, mutually balance their expressions in ECs. Full article

(This article belongs to the Special Issue Angiogenesis Inhibitors)

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Pharmaceuticals, Volume 4, Issue 6 (June 2011) – 8 articles , Pages 782-949

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