Immunohistochemical Evidence for Glutamatergic Regulation of Nesfatin-1 Neurons in the Rat Hypothalamus

Nesfatin-1, identified as an anorexigenic peptide, regulates the energy metabolism by suppressing food intake. The majority of nesfatin-1-synthesizing neurons are concentrated in various hypothalamic nuclei, especially in the supraoptic (SON), arcuate (ARC) and paraventricular nuclei (PVN). We tested the hypothesis that the glutamatergic system regulates nesfatin-1 neurons through glutamate receptors. Therefore, the first aim of the proposed studies was to examine effects of different glutamate agonists in the activation of nesfatin-1 neurons using c-Fos double immunohistochemical labeling. Experimental groups were formed containing male and female rats which received intraperitoneal injections of glutamate agonists kainic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) while the control rats received vehicle. The significant increase in the number of c-Fos-expressing nesfatin-1 neurons after agonist injections were observed both in female and male subjects and some of these effects were found to be sexually dimorphic. In addition, treatment with specific glutamate antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or dizocilpine (MK-801) before each of the three agonist injections caused a statistically significant reduction in the number of activated nesfatin-1 neurons in the hypothalamic nuclei including supraoptic, paraventricular and arcuate nuclei. The second aim of the study was to determine the expression of glutamate receptor subunit proteins in the nesfatin-1 neurons by using a double immunofluorescence technique. The results showed that the glutamate receptor subunits, which may form homomeric or heteromeric functional receptor channels, were expressed in the nesfatin-1 neurons. In conclusion, the results of this study suggest that nesfatin-1 neurons respond to glutamatergic signals in the form of neuronal activation and that the glutamate receptors that are synthesized by nesfatin-1 neurons may participate in the glutamatergic regulation of these neurons.

Effects of atenolol injected into the nucleus accumbens septi in rats in the elevated plus-maze test

BackgroundIn previous studies, we have observed that glutamate antagonists injected within the nucleus accumbens septi (NAS) induced an anxiolytic-like effect in the elevated plus maze (EPM) test in rats. In the present study, the effect of Atenolol, a specific Beta Adreno-receptor antagonist in the EPM was studied in male rats bilaterally cannulated NAS.MethodsRats were divided into five groups that received either 1 μL injections of saline or atenolol in different doses (0.75, 1 or 2 μg/1 μL, n=15–16) 15 min before testing.ResultsTime Spent in the Open Arm was modified by treatment (F=4.563, p=0.006, df 3). This was increased by the lowest dose of atenolol (p<0.05), by the medium doses (p<0.001) and also by the highest dose (p<0.01). Time per Entry was modified by treatment (F=4.54, p=0.06, df 3). This parameter was increased by the lowest dose of atenolol (p<0.01), but not for the medium and higher doses.ConclusionsWe conclude that Atenolol beta receptor blockade in the accumbens lead to an anxiolytic-like effect related to an increase in the time spent in the open arm and in the time per entry, showing specific behavioral patterns.

The Effect of Kynurenic Acid on Apoptosis in Hepatocellular Carcinoma

Kynurenic Acid (KYNA) is a metabolite of tryptophan pathway and also an endogenous antagonist of glutamate receptors. Several studies indicated that glutamate antagonists have anti-proliferative potential. Moreover, subunits of the NMDA receptor which is one of the glutamate receptors have been shown to be found in human hepatocellular carcinoma cell line (HepG2). In this study, the antitumor effects of KYNA in HepG2 cells were investigated for the first time at the molecular level. The effects of KYNA on the viability of HepG2 cells were determined by MTT analyses. Effects of KYNA on mRNA transcriptions of apoptosis related genes Bax, Bcl-2 and Caspase-3 were analyzed by qRT-PCR. mRNA expression analysis revealed that the mRNA levels of effector Caspase-3 and pro-apoptotic Bax/Bcl-2 ratio were not increased in HepG2 cells treated with KYNA. In conclusion, our findings showed that KYNA does not exert its anti-proliferative effects on HepG2 cells through caspase-mediated apoptotic cell death, but it may perform this anti-proliferative effect through a different mechanism of death. Further studies are needed to find out potential cell death mechanisms that may play a role in anti-proliferative activity of KYNA on HepG2 cells.

Other Agents (Glutamate Antagonists, Antihistamines, Melatonin Agonists, and Others)

A final drug class of other agents includes glutamate antagonists, antihistamines, and melatonin agonists. These agents have a range of clinical uses, but most are used symptomatically to produce sedation or reduce anxiety or for other symptoms. The clinical pharmacology of specific agents within each class, including their efficacy and side effects, is explored. Specific phenomena surveyed include the inefficacy of novel anticonvulsants for mood: clinicians and researchers have been excited about novel anticonvulsants, most of which have either anti-glutamate or pro-GABA effects. None have proven effective for affective illness or for any important psychiatric use, except perhaps for some mild anxiolytic effects for the GABAergic agents. The purported benefits of ketamine are also investigated.

Retraction: Radenovic L, Selakovic V, Janac B, Todorovic D. Effect of glutamate antagonists effect on nitric oxide production in rat brain following intrahippocampal injection, Arch Biol Sci. 2007;59(1):29-36, DOI: 10.2298/ABS0701029R

This is a notice of retraction of the article: Effect of glutamate antagonists effect on nitric oxide production in rat brain following intrahippocampal injection, published in the Archives of Biological Sciences in 2007, Vol. 59, Issue 1. The Editor-in-Chief has been informed that this paper plagiarizes an earlier paper: Radenovic L, Selakovic V. Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection. Brain Res Bull. 2005;67(1-2):133-41. The results presented in the article that is being retracted overlap with the results presented in the original article without appropriate justification, permission or crossreferencing. After confirmation of this fact, the Editor-in-Chief of the Archives of Biological Sciences has decided to retract the paper immediately. We apologize to the readers of the journal that it took so many years to notice this error and to retract the paper. We request readers of the journal to directly get in touch with the editorial office and the editors of the journal for similar cases in the future, so that they can be handled promptly. <br><br><font color="red"><b> Link to the retracted article <u><a href="http://dx.doi.org/10.2298/ABS0701029R">10.2298/ABS0701029R</a></b></u>

Amethystic agents influencing toxicodynamics of ethanol

The pathogenetic mechanisms of acute alcoholic intoxications are examined and is based the expediency of the search for the amethystic agents, which influence neurotransmitter systems. Promising should be considered the agents, which modulate GABA-systems (partial reverse agonists of benzodiazepine receptors), glutamate (antagonists of metabotropic receptors mGluR2/3), opioid neuropeptides (antagonists of opioid receptors), acetylcholine (reversible inhibitors of acetylcholinesterase and M-cholinoagonists), adenosine (selective antagonists of A -receptors). The amethystic effect manifest also the substances, which modify the second messengers systems (calcium, nitrergic and cascade of arachidonic acid). The most of the means examined possesses the moderate amethystic potential, and effectiveness is manifested predominantly during the preventive application.

Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system

Neuropathic pain refers to chronic pain that results from injury to the nervous system. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central phenomena. Although numerous pharmacological agents are available for the treatment of neuropathic pain, definitive drug therapy has remained elusive. Recent drug discovery efforts have identified an original neurobiological approach to the pathophysiology of neuropathic pain. The development of innovative pharmacological strategies has led to the identification of new promising pharmacological targets, including glutamate antagonists, microglia inhibitors and, interestingly, endogenous ligands of cannabinoids and the transient receptor potential vanilloid type 1 (TRPV1). Endocannabinoids (ECs), endovanilloids and the enzymes that regulate their metabolism represent promising pharmacological targets for the development of a successful pain treatment. This review is an update of the relationship between cannabinoid receptors (CB1) and TRPV1 channels and their possible implications for neuropathic pain. The data are focused on endogenous spinal mechanisms of pain control by anandamide, and the current and emerging pharmacotherapeutic approaches that benefit from the pharmacological modulation of spinal EC and/or endovanilloid systems under chronic pain conditions will be discussed.