Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

Objective: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. Methods: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. Results: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. Conclusion: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review.

OBJECTIVE: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. METHODS: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. RESULTS: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. CONCLUSION: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Kinetic properties of Streptomyces canarius L- Glutaminase and its anticancer efficiency

Abstract L-glutaminase was produced by Streptomyces canarius FR (KC460654) with an apparent molecular mass of 44 kDa. It has 17.9 purification fold with a final specific activity 132.2 U/mg proteins and 28% yield recovery. The purified L-glutaminase showed a maximal activity against L-glutamine when incubated at pH 8.0 at 40 °C for 30 min. It maintained its stability at wide range of pH from 5.0 11.0 and thermal stable up to 60 °C with Tm value 57.5 °C. It has high affinity and catalytic activity for L-glutamine (Km 0.129 mM, Vmax 2.02 U/mg/min), followed by L-asparagine and L-aspartic acid. In vivo, L-glutaminase showed no observed changes in liver; kidney functions; hematological parameters and slight effect on RBCs and level of platelets after 10 days of rabbit's injection. The anticancer activity of L-glutaminase was also tested against five types of human cancer cell lines using MTT assay in vitro. L-glutaminase has a significant efficiency against Hep-G2 cell (IC50, 6.8 μg/mL) and HeLa cells (IC50, 8.3 μg/mL), while the growth of MCF-7 cells was not affected. L-glutaminase has a moderate cytotoxic effect against HCT-116 cell (IC50, 64.7 μg/mL) and RAW 264.7 cell (IC50, 59.3 μg/mL).

Beta-amyloid treatment sensitizes mice to amphetamine-induced locomotion but reduces response to caffeine.

BACKGROUND: Psychosis frequently occurs in Alzheimer's disease (AD), being associated with more severe cognitive decline, but the underlying mechanisms are unknown. OBJECTIVE: To investigate the effect of centrally administered beta-amyloid peptide, a model for AD, in the locomotor response to amphetamine, caffeine and MK-801, which are psychoactive drugs related to neurochemical changes occurring in psychosis. METHODS: Mice were intracerebroventricularly injected with beta-amyloid (25-35), and after 1 week they were tested in the passive avoidance, spontaneous alternation and locomotor tasks. RESULTS: Besides impaired performance in inhibitory avoidance and spontaneous alternation tasks, beta-amyloid-treated mice showed increased spontaneous locomotion, augmented response to amphetamine (1.5 mg/kg), blunted response to caffeine (30 mg/kg) and no difference in MK-801 (0.25 mg/kg)-induced locomotor activation when compared to its respective control. CONCLUSION: These results are compatible with the hypothesis that beta-amyloid peptide may predispose to psychotic symptoms of AD by increasing sensitivity of the dopaminergic system, possibly related to a decreased adenosinergic inhibitory tone.

Action of 4-aminopyridine on extracellular amino acids in hippocampus and entorhinal cortex: a dual microdialysis and electroencehalographic study in awake rats.

In order to study the role of amino acids in the hippocampus and the entorhinal cortex during the convulsive process induced by 4-aminopyridine (4-AP), we have used a device allowing the simultaneous microdialysis and the recording of their electrical activity of both regions in freely moving rats. We found that infusion of 4-AP into the entorhinal cortex resulted in a large increase in extracellular glutamate and glutamine and small increases in glycine and taurine levels. Likewise, infusion of 4-AP into the hippocampus resulted in a major increase in glutamate, as well as slight increases in taurine and glycine. In both infused regions the peak concentration of extracellular glutamate was observed 15 min after 4-AP administration. No significant changes were found in the non-infused hippocampus or entorhinal cortex of the same rats. Simultaneous electroencephalographic recordings showed intense epileptiform activity starting during 4-AP infusion and lasting for the rest of the experiment (1 h) in both the entorhinal cortex and the hippocampus. The discharges were characterized by poly-spikes and spike-wave complexes that propagated almost immediately to the other region studied. These findings suggest that increased glutamatergic synaptic function in the circuit that connects both regions is involved in the epileptic seizures induced by 4-AP.

Dissimilar effects of lithium and valproic acid on GABA and glutamine concentrations in rat cerebrospinal fluid.

1. This study compared the effects of the antimanic drugs, lithium and valproic acid, on GABA and glutamine CSF concentration and on head-shakes during hyponatremia. 2. Hyponatremic and normonatremic rats were treated with 2 mEq/kg lithium and 360 mg/kg valproic acid. Behavioral observation was conducted for 120 min after which blood and CSF collection were performed under anesthesia. 3. Peritoneal dialysis with glucose induced moderate hyponatremia and doubled glutamine CSF concentrations. Both lithium and valproic acid significantly increased GABA CSF levels in normonatremic and hyponatremic animals. Valproic acid induced head-shakes and increased CSF glutamine concentration. 4. The results suggest that both antimanic drugs have similar effects on GABA, but lithium is preferred if the increase in glutamine concentration poses a problem, either in the presence or absence of hyponatremia.

Effect of adrenaline on lymphocyte metabolism and function. A mechanism involving cAMP and hydrogen peroxide.

This study examined the effect of adrenaline on lymphocyte metabolism and function. The following parameters were addressed: cell proliferation, glucose and glutamine metabolism as indicated by the measurement of enzyme activities, the utilization of metabolites and production and oxidation of substrates. We also evaluated the involvement of beta-receptors in this response as well as the possible effect of cAMP and hydrogen peroxide in the process of lymphocyte activation by adrenaline. The results indicated that adrenaline is able to induce metabolic changes in lymphocytes that are related to enhanced proliferative capacity, but under physiological conditions fails to initiate the process, the catecholamine could, increase cell proliferation via increased production of H2O2 by macrophages, since this reactive oxygen intermediate can act as a trigger for lymphocyte activation. The results also showed that distinct populations of lymphocytes present different responses to adrenaline activation, as demonstrated by cells obtained from the same site but exposed to different mitogens such as LPS and ConA.

Cotransport of sodium with glutamine, alanine and glucose in the isolated rabbit ileal mucosa.

To investigate the effect of substrates during oral rehydration therapy, we studied intestinal cation cotransport (ICC) with glutamine (Gln), alanine (Ala) and glucose (Glu). The specific aims were to determine the biological effects of these three different cotransport systems on intestinal function. Isolated rabbit ileal mucosa preparations mounted in Ussing chambers were studied. ICC was determined by measuring short-circuit current (Isc) and potential difference (PD) while monitoring tissue resistance (TR). The data are reported as the mean +/- SEM of 4-6 experiments for each amino acid concentration. Increasing concentrations of Gln (10(-5) to 10(-2) M), Ala (10(-5) to 10(-1) M) and Glu (10(-5) to 10(-2) M) caused a significant (P < 0.05) increase in ICC. Gln (30 mM) and Ala (0.1 M) had a maximal effect (Em(Gln) = 100% and Em(Ala) = 66%, P < 0.05) which was higher than that obtained with 30 mM Glu (Em(Glu) = 35%). When sodium was replaced with choline on the mucosal side, Ringer solution completely abolished the response with Gln, Ala and Glu. The presence of all three substrates (10(-2) M Gln, 10(-1) M Ala, and 10(-2) M Glu) in Ringer solution on the mucosal side caused a significant increase in ICC (delta increase of short circuit current = 111 +/- 43 microA, P < 0.05). These results demonstrate that Gln, Ala and Glu each increased sodium-dependent cation cotransport, and that sodium-dependent intestinal cation cotransport was higher with Gln than with Ala or Glu.