Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

Differential Protective Effect of Zinc and Magnesium for the Hepatic and Renal Toxicity Induced by Acetaminophen and Potentiated with Ciprofloxacin in Rats.

Background and Objectives: The purpose of this study was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally induced with acetaminophen (AAPh) and potentiated by a ciprofloxacin addition in rats. Material and Methods: The experiment was performed on five animal groups: group 1-control, treated for 6 weeks with normal saline, 1 mL/kg; group 2-AAPh, treated for 6 weeks with AAPh, 100 mg/kg/day; group 3-AAPh + C, treated for 6 weeks with AAPh 100 mg/kg/day and ciprofloxacin 50 mg/kg/day, only in the last 14 days of the experiment; group 4-AAPh + C + Mg, with the same treatment as group 3, but in the last 14 days, MgCl2 10 mg/ kg/day was added; and group 5-AAPh + C + Zn, with the same treatment as group 3, but in the last 14 days, zinc gluconate (ZnG), 10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (p < 0.001 group 2 vs. group 1 for all mentioned parameters). Furthermore, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, at 0.001 < p < 0.01 and 0.01 < p < 0.05, respectively). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days, resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine (0.01 < p < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against the increase in liver enzymes, and a more pronounced protection against the increase in serum urea and creatinine (0.001 < p < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < p < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in the case of ZnG, to a higher extent, especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < p < 0.05 group 5 vs. group 4). Conclusions: This study presents further proof for the beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney's function, and the antioxidant profile improvement has a key role, especially in the case of zinc gluconate.

An exploratory study on the association between blood-based biomarkers and subacute neurometabolic changes following mild traumatic brain injury.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers and advanced neuroimaging modalities such as magnetic resonance spectroscopy (MRS) or diffusion tensor imaging (DTI) have enhanced our understanding of the pathophysiology of mild traumatic brain injury (mTBI). However, there is limited published data on how blood biomarkers relate to neuroimaging biomarkers post-mTBI. METHODS: To investigate this, 30 patients with mTBI and 21 healthy controls were enrolled. Data was collected at two timepoints postinjury: acute, < 24 h, (blood) and subacute, four-to-six weeks, (blood and imaging). Interleukin (IL) 6 and 10 (inflammation), free thiols (systemic oxidative stress) and neurofilament light (NF-L) (axonal injury) were quantified in plasma. The neurometabolites total N-acetyl aspartate (tNAA) (neuronal energetics), Myo-Inositol (Ins) and total Choline (tCh) (inflammation) and, Glutathione (GSH, oxidative stress) were quantified using MRS. RESULTS: Concentrations of IL-6 and IL-10 were significantly elevated in the acute phase post-mTBI, while NF-L was elevated only in the subacute phase. Total NAA was lowered in patients with mTBI, although this difference was only nominally significant (uncorrected P < 0.05). Within the patient group, acute IL-6 and subacute tNAA levels were negatively associated (r = - 0.46, uncorrected-P = 0.01), albeit not at a threshold corrected for multiple testing (corrected-P = 0.17). When age was added as a covariate a significant increase in correlation magnitude was observed (ρ = - 0.54, corrected-P = 0.03). CONCLUSION: This study demonstrates potential associations between the intensity of the inflammatory response in the acute phase post-mTBI and neurometabolic perturbations in the subacute phase. Future studies should assess the longitudinal dynamics of blood-based and imaging biomarkers after injury.

Improvement in serum lipids and liver morphology after supplementation of the diet with fish oil is more evident under regular feeding conditions than under high-fat or mixed diets in rats.

BACKGROUND: Dietary n- 3 polyunsaturated fatty acids (PUFAs) have a role in preventing cardiovascular and hepatic diseases. However, their effects might differ significantly depending on individual dietary patterns. The aim of the present study was to evaluate the effects of dietary supplementation with ω-3 fatty acids (FA), administered in different schedules, on hepatic and aortic histological structure, lipid profile, and body weight (BW) in male Wistar rats under standard (SD), high-fat diet (HFD) and mixed feeding conditions. METHODS: PUFA treatment consisted of the administration of 50 mg/kg fish oil (FO) daily by oral gavage. HFD was obtained by adding a suspension of 4% cholesterol, thiouracil and cholic acid to the animals' drinking water. The rats were maintained on the diets for 6 weeks, and different schedules of PUFA administration were used. At 14, 28, and 42 days, the morphology of liver and aortic samples and the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) were assessed. RESULTS: The HFD groups exhibited significant hyperlipidemia and aortic inflammation, with progression to atherogenesis after 6 weeks. Administration of PUFAs slightly attenuated the aortic changes in these groups and reduced the liver's tendency to steatosis. FO-induced metabolic improvement was more evident in SD than in HFD rats. For instance, after the first 2 weeks, SD animals that received PUFAs had significantly increased HDL levels vs. controls (62.375 ± 4.10 vs. 52.625 ± 8.38 mg/dL, P < 0.05), but HFD rats did not, and decreased TG levels were observed exclusively in the SD rats (57.6 ± 4.09 vs. 66 ± 4.69 mg/dL, P < 0.05). After 6 weeks of n- 3 PUFA administration, LDL was significantly lower in the SD rats than in controls (13.67 ± 4.13 vs. 30.83 ± 2.86 mg/dL, P < 0.001), but the decrease in the HFD rats, although significant (49.17 ± 5.85 mg/dL vs. 57.17 ± 4.96 g/dL, P < 0.05), was not as marked. In the mixed-diet groups, administration of 50 mg/kg/day FO for 14 days under SD conditions following 4 weeks of HFD slightly decreased TG (86.625 ± 11.67 vs. 73 ± 4.52 mg/dL, P < 0.05) and increased HDL (45.875 ± 5.28 vs. 56 ± 3.16 mg/dL). However, in these animals, n-3 PUFA administration had no effect on LDL or TC. Administration of half of the above dose failed to improve any biochemical parameters. FO protected against excessive weight gain mainly under SD conditions. CONCLUSIONS: The results show that FO confers more protection against cardiovascular risk factors (increased LDL and TG, decreased HDL) and liver lipid accumulation when given to rats consuming regular diets than when given to rats consuming a high-fat diet. This argues that priority should be given to consumption of a healthy diet rather than to the use of supplements. The effectiveness of n-3 PUFAs might be reduced in the case of hyperlipidic intake or after consumption of a high-fat diet.

Chromium picolinate reduces morphine-dependence in rats, while increasing brain serotonin levels.

Chromium is an essential trace element with anti-diabetic and anti-depressant effect; the latter is considered related to chromium properties of increasing brain serotonin. Cr3+ salts were shown to improve some forced swimming-parameters and to induce rewarding effects, which are additive to those of morphine, but Cr effect on addictive processes has not been tested. AIM: The present study aimed to assess chromium picolinate (CrPi) influence on morphine-dependence in rats. MATHERIAL AND METHODS: We used five groups of 10 rats. Groups 1 and 2 (controls) received saline, respectively CrPi, 0.01 mg/kg/day, for 10 days. In groups 3, 4 and 5 dependence was induced with progressively-increased morphine doses (from 5 - day 1-90 mg/kg/day - day 10, s.c.). Group 3 received only morphine, while groups 4 and 5 received CrPi, i.p., 10 and respectively 5 µg/kg/day, during the 10 days of dependence induction. On day 11, groups 3, 4, and 5 were administered 90 mg/kg morphine, and, 2 h later, all rats received naloxone, 2 mg/kg s.c., to precipitate withdrawal. We compared withdrawal intensity in group 3 vs. groups 4 and 5, assessing both individual symptoms and Gellert-Holtzman global withdrawal score. Upon rats sacrifice at the end of the experiments, brain serotonin (5HT) in certain areas and serum Cr were assessed. RESULTS: Some withdrawal signs were unequally influenced by CrPi: compulsive mastication was reduced by both CrPi doses (p < 0.05), while teeth chattering and grooming were significantly reduced only by the higher dose (p < 0.05). Withdrawal score was reduced by both CrPi doses: from 132.4 ±â€¯9.87 - group 3 to 122.2 ±â€¯6.47 - group 4 (p < 0.01 vs. group 3) and 124.1 ±â€¯8.41 - group 5 (p < 0.05 vs. group 3). CrPi reduction of withdrawal is accompanied by increased brain 5 H T, mainly in the prefrontal cortex (646.3 ±â€¯8.51 - group 3 vs. 661.5 ±â€¯14.63 - group 4, p < 0.01 and 660.7 ±â€¯14.01 pg/mg tissue - group 5, p < 0.05 vs. group 3). CrPi also increases brain 5 H T in non-dependent rats (prefrontal cortex: 541.6 ±â€¯31.80, group 1 and 565.5 ±â€¯16. 46 pg/mg tissue, group 2, p < 0.05). Administration of CrPi determined a dose-dependent increase of serum Cr. CONCLUSIONS: Our study evidenced a slight, but significant reduction of morphine dependence in rats induced by chromium picolinate, accompanied by increased brain serotonin. This might be considered a supplementary evidence for chromium anti-depressant effect and its serotonin-mediated mechanisms.

Experimental Research Showing the Reduction of Naloxone-Place Aversion by Oral Zinc Administration in Rats.

Previous studies showed the attenuation of both morphine-dependence and morphine-place preference by zinc. Conditioned place preference and aversion are experimental models frequently used to test the reward-stimulating, respectively the aversive effects induced by different stimuli or substances. Addictive substances usually induce place preference (exhibit reward-stimulating properties), while their antagonists determine place-avoidance (aversion). The present study aimed to assess the effect determined by zinc sulphate oral administration (2 and 4 mg/kg/day, 14 days, prior to habituation) on the place aversion induced by two naloxone doses (1.5 and 2.5 mg/kg/administration). The results show a robust, dose-dependent reduction of the aversion determined by both naloxone doses (the aversion induced by 1.5 mg/kg naloxone was reduced with 15%-the lower zinc dose and with 24%-the higher zinc dose; the aversion induced by 2.5 mg/kg naloxone was reduced with 16%-the lower zinc dose and with 29%-the higher zinc dose). This represents a new proof of the interactions between zinc and opioidergic system and a further argument for dietary zinc supplementation in patients on opioids for cancer-related chronic pain.

Zinc involvement in opioid addiction and analgesia--should zinc supplementation be recommended for opioid-treated persons?

INTRODUCTION: Zinc chelators were shown to facilitate some opioid-withdrawal signs in animals. Zinc deficiency, which affects more than 15% the world's population, is also common among opioid consumers and opioid-treated animals exhibit misbalances of zinc distribution. AIM: The present study focuses on how zinc ions interfere with opioid dependence/addiction and analgesia, trying to preliminary discuss if zinc supplementation in opioid-users should be recommended in order to reduce the risk of addiction. METHODS: All relevant literature was searched up to April 2015. The search was performed using the term "zinc" plus combinations of following terms: "opioid receptors", "opioid" or representatives of this class, "addiction", "dependence", "analgesia", and "pain". Human, animal, in vitro studies and reviews were including. RESULTS: Both human and animal studies revealed decreased serum zinc under opioid-administration conditions, attributed mainly to increased urinary elimination (humans) or redistribution (animals). Moreover, animal studies revealed decreased brain zinc levels in morphine-treated animals, with increased zinc hepatic levels, but also an enhancement of endogenous opioid system activity and a possible reduction of morphine withdrawal by zinc. In vitro studies revealed reduction of opioid ligands binding to receptors by zinc. However, the very few in vivo animal studies on opioid analgesia revealed controversial results, as zinc demonstrated clear analgesic effect, but zinc associated to opioids doesn't result in a potentiation of the analgesic effect. CONCLUSION: Zinc dietary supplementation in patients treated with opioids for cancer-related chronic pain should be considered, due to the high incidence of zinc deficiency, also well-documented in opioid consumers. The low toxicity of orally-administered zinc also pleads for this idea. The main contra-argument to zinc administration in opioid-treated persons is related to the way zinc influences opioid-induced analgesia.

Sertraline influence on morphine-induced conditioned place preference in rats.

UNLABELLED: Serotonine reuptake inhibitors are an important pharmacological arsenal for treating major depression, a severe disease with poorly understood pathogenic mechanisms. Also, little is known about the action of antidepressants on reward system, the function of which is severely affected in this disorder. AIM: To assess the influence of sertraline on brain reward system by conditioned place preference technique in rats. RESULTS: Both 3 and 5 mg/kg doses of sertraline determined a significant rewarding effect, whereas only the 5 mg/kg dose increased the morphine-induced rewarding effect (in the morphine-only group time spent in the conditioning chamber increased by 184.92 +/- 21.43% post-conditioning vs. preconditioning, whereas the increase was 195.56 +/- 18.3% in the group treated with morphine and sertraline 5 mg/kg, p < 0.05). CONCLUSIONS: The stimulant effect of sertraline on brain reward function might be involved in its therapeutic efficacy.

Manganese interactions with dopaminergic system.

Manganese is a trace element with important involvement in the central nervous system functioning. The effects of manganese excess on central dopaminergic system in case of both basal nuclei and reward system are linked to important pathologic states such as Parkinsonism and cognitive impairment. Our data show that Mn2+ reduces the intensity of experimental morphine addiction in rats (manganese chloride unequally decreases several symptoms of opioid withdrawal syndrome - signs such as compulsive mastication, grooming and teeth chattering being particularly affected). Manganese chloride, administered during conditioning acquisition phase in rats, significantly reduces the intensity of morphine conditioned place preference. We believe that manganese interaction with dopaminergic circuits in the brain reward system represents one of the most important aspects of the action of bivalent cations at central nervous system level.

Behavioral involvement of imidazoline system.

The imidazoline system consists in imidazoline receptors I1, I2 and I3 and the active as well as that there are some endogenous ligands. We consider that one of the most important functions of this system is modulation of different types of behavior. Existent data show that I1 and I2 receptors have different effects on some behavior components, such as suicidal behavior, stress, anxiety, food intake etc. We consider that selective I1 and I2 agonists could become drugs to be used in the therapy of some behavioral disorders. The fact that some agonists or antagonists of imidazoline receptors have also effect on alpha-adrenergic receptors or MAO (monoamine oxidase) enlarges the use area of the compounds in behavioral disorders.

Involvement of imidazoline system in drug addiction.

The imidazoline system (a concept which is barely over decades old) consists in imidazoline receptors I, I2 and I3 and their active endogenous ligands, the most important of which is agmatine. Brain contains both I1 and 12 of imidazoline receptors. One of the most important functions of this system is modulation of different behaviour components, such as suicidal behaviour, stress, anxiety, food intake etc. Own data preliminary data revealed different effects of alpha2 and imidazoline-receptors antagonists on morphine conditioned place preference (efaroxan reduces its intensity, while idazoxan has no influence); this reveals a possible di fferent role of I1 and I2 receptors in reward system.

Research on serum and saliva concentration of some bivalent cations in patient with suppurations of the oro-maxillo-facial area.

UNLABELLED: Bivalent cations, such as calcium, magnesium, zinc, copper and manganese play important roles in some physiological and pathological processes on the human body. AIM: To determine possible modifications in serum and saliva concentration of total-Ca2+, total-Mg2+, Zn2+ and Cu2+ in patients with suppurative infections of the oro-maxillo-facial area and eventually their significance for the mentioned pathology. MATERIAL AND METHOD: Study included 47 patients with suppurative infections of the oro-maxillo-facial area, hospitalised during 2006-2008 in the oro-maxillo-facial clinic of "Sfântul Spiridon" Hospital Iasi and 43 healthy control volunteers. RESULTS: Results revealed decreased serum Zn2+ (0.94 +/- 0.21 vs. 1.39 +/- 0.14 mg/L, p < 0.01), decreased serum Zn2+/Cu2+ ratio and increased serum and saliva total-Mg2+ concentration (27.34 +/- 2.61 mg/mL in patients vs. 23.83 +/- 1.61 mg/L in healthy controls- serum, p < 0.05 and 3.79 +/- 0.41 mg/mL in patients vs. 3.21 +/- 0.40 mg/mL in healthy controls - saliva, p < 0.05) in patients with suppurative infections of the oro-maxillo-facial area vs. healthy controls. There were no statistically significant differences in total-Ca2+ concentrations in saliva and serum. Our data are in agreement with medical literature revealing zinc deficiency as a predisposition factor to infection. CONCLUSION: We consider that a significant increase in total-Mg2+ saliva concentration, as well as a decrease in Zn2+/Cu2+ serum ratio could be considered a marker for predisposition to oro-maxillar suppurations.

Magnesium and other bivalent cations influence upon sodium montelukast effect in experimental-induced thermoalgesia.

We tested the influence of magnesium, zinc and copper upon the montelukast (MK, antagonist of cysteinyl leukotriene receptor type 1) effect in experimentally-induced thermoalgesia. We worked on 5 groups of 10 adults, each Wistar rats, that received: group I-control; group II: MK (10 mg/kg) unique administration; group III: MgCl2 (1 mM/kg/day) i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day; group IV: ZnCl2, (0.1 mM/kg/day), i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day; group V: copper acetate (0.05 mM/kg/day), i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day. We determined the thermoalgesic sensitivity (TS) using a tail flick analgesia meter, initially, 3 days after daily cation administration and 3 hours after MK administration. Our data show that MK has a statistically significant reduction of TS vs control group (3.76 +/- 1.04 s vs 1.81 +/- 0.98 s, p < 0.05). Copper and magnesium administration do not significantly change the MK effect to decrease TS. The co-administration of zinc and MK statistically significantly increased the TS of the group that received only MK (2.51 +/- 0.21 s vs 3.76 +/- 1.04 s, p < 0.05). Animals that received only cations (in the above mentioned doses) did not significantly change TS.

[Zinc involvements in the brain]. / Implicatii ale zincului la nivelul creierului.

Central nervous system (CNS) concentrates almost 10% of total zinc in the human body. Imbalances in zinc concentration are associated with numerous CNS diseases. Zinc deficiency is associated with nervous anorexia, major depression, cognitive impairment, and uncontrolled behavior. Our data reveal that plasma zinc concentration is decreased in major depression and it significantly increases following sertraline or amitriptyline treatment. Also, we found that ZnCl2 administration while inducing morphine-dependence in rats significantly decreases the symptoms of opioid-withdrawal syndrome. Recent data incriminate zinc deficit in the development of encephalopathy following severe impairment of hepatic function. On the other hand, zinc content of certain brain areas in Alzheimer disease is twice that in controls. Parkinson disease is also associated with higher zinc concentrations in the brain than normal. The ratio plasma zinc- other bivalent cations is also important for normal brain function.