Effect of Acute and Chronic Administration of l-Tyrosine on Nerve Growth Factor Levels in Rat Brain

Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Neurological manifestations are variable and some patients are developmentally normal, while others show different degrees of developmental retardation. Considering that current data do not eliminate the possibility that elevated levels of tyrosine and/or its derivatives may have noxious effects on central nervous system development in some patients, the present study evaluated nerve growth factor (NGF) levels in hippocampus, striatum and posterior cortex of young rats. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal administration of l-tyrosine (500 mg/kg) or saline. Chronic administration consisted of l-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); the rats were killed 12 h after the last injection. NGF levels were then evaluated. Our findings showed that acute administration of l-tyrosine decreased NGF levels in striatum of 10-day-old rats. In the 30-day-old rats, NGF levels were decreased in hippocampus and posterior cortex. On the other hand, chronic administration of l-tyrosine increased NGF levels in posterior cortex. Decreased NGF may impair growth, differentiation, survival and maintenance of neurons.     

Intra-striatal estradiol in female rats impairs response learning within two hours of treatment

Estradiol treatment administered systemically or directly to the dorsolateral striatum across two days impairs performance on a response task in which rats learn to make a specific body turn to locate food on a maze. Estradiol can act through both slow and rapid signaling pathways to regulate learning impairments, however it is impossible to dissociate the slow from the rapid contributions of estradiol following long exposures. To assess the rapid effects of estradiol on striatum-sensitive learning, we trained rats on a response learning task after either relatively short or long treatments of estradiol infused directly into the striatum. Three-month-old female rats were ovariectomized 21 days before training and received guide cannulae implanted bilaterally into the dorsolateral striatum. For short duration treatments, rats were given bilateral infusions (0.5 μl) of 17β-estradiol-sulfate (0, 5, 50, or 500 nM in aCSF-vehicle) either 2 h or 15 min prior to training. For long duration treatments, rats received a series of estradiol infusions (500 nM) at 48, 24, and 2 h prior to training. Replicating previous findings (Zurkovsky et al., 2007), intra-striatal estradiol treatments given for two days prior to training impaired response learning. Estradiol-induced impairments in performance were also demonstrated 2 h, but not 15 min, after single infusions. Thus, estradiol acts within hours of exposure in the striatum, a structure lacking classical estrogen receptors, to impair response learning.     

Cadmium effects on 24 h changes in glutamate,aspartate, glutamine,GABA and taurine content of rat striatum

This work evaluates the possible changes in 24 h variations of striatal aspartate, glutamate, glutamine, gamma-aminobutyric acid (GABA) and taurine content after oral cadmium treatment. Male rats were submitted to cadmium exposure at two doses (25 and 50 mg/L of cadmium chloride (CdCl₂)) in the drinking water for 30 days. Control rats received cadmium-free water. After the treatment, rats were killed at six different time intervals throughout a 24 h cycle. Differential effects of cadmium on 24 h amino acid fluctuations were observed. Metal exposure modified the daily pattern of the amino acids concentration found in control animals, except for GABA and taurine with the lowest dose used. Exposure to 25 mg/L of CdCl₂ decreased mean content of aspartate, as well as GABA concentration. These results suggest that cadmium exposure affects 24 h changes of the studied amino acids concentration in the striatum, and those changes may be related to alterations in striatal function.     

The role of the angiotensin AT2 receptor on the diurnal variations of nociception and motor coordination in rats

Phasic pain demonstrates significant diurnal variation in rats. Angiotensin II modulates pain transmission and the diurnal variation in nociception in several rodent pain models. The participation of AT2 receptors in the diurnal regulation of nociception is not yet elucidated. In the present study we investigated the effects of selective peptide AT2 agonist CGP 42112A and the nonpeptide AT2 receptor antagonist PD 123319 on the nociception, motor coordination and arterial blood pressure. Male Wistar 12 weeks old rats were used. CGP 42112A was injected at single doses of 1 and 5 μg/rat intracerebroventricularly (ICV) and infused chronically ICV at a dose of 12 μg/rat/day during 14 days by osmotic minipumps. PD123319 was injected at single doses of 1 and 5 μg/rat, ICV and chronically subcutaneously at a dose of 10 mg/kg/day/14 days. Nociception was assessed by an analgesimeter, arterial blood pressure (ABP) was measured by tail cuff method, and motor coordination by Rota-rod method. Single doses of CGP 42112A (1 and 5 μg/rat) provoked a short lasting antinociception. Unlike acute injection, chronic CGP 42112A infusion increased nociception at the beginning and the end of light phase thus attenuating the diurnal variations observed in the controls. Moreover, it produced an increase of ABP and improved motor coordination. Both acute (1 μg/rat) and chronic PD 123319 treatment resulted in a decrease of pain threshold and chronic treatment attenuated its diurnal fluctuation. Our data support a role for Ang II type 2 receptors in the control of diurnal variations of nociception in rats.     

Rat electropharmacograms of the flavonoids rutin and quercetin in comparison to those of moclobemide and clinically used reference drugs suggest antidepressive and/or neuroprotective action

In order to be able to test single constituents of herbal plant extracts with respect to possible clinical usefulness, the model of local field potential analysis leading to the so-called electropharmacogram has been successfully used in rats to classify the effects of theanine and theogallin in the past. The present investigation aims at the prediction of efficacy and possible mechanisms of action of rutin and quercetin. Adult rats (day–night converted) were instrumented with four bipolar concentric electrodes into the frontal cortex, hippocampus, striatum and reticular formation. Field potentials were recorded during a pre-drug reference period of 45 min followed by oral administration of the particular test compound and 4 h recording thereafter. Data were transmitted wirelessly to the computer for spectral frequency analysis. Rutin (5–80 mg/kg) as well as quercetin (5–40 mg/kg orally) produced similar electropharmacograms with dose dependent decreases of spectral alpha2 and beta1 frequencies within all brain areas. Peak effects were reached 4 h after administration. The pattern of changes approached that obtained after 2.5 mg/kg of moclobemide during the first hour as revealed by discriminant analysis in comparison to a large matrix of other drugs with known clinical indications. Data suggest antidepressant capabilities for rutin and quercetin with inhibition of monoamino oxidase at least as part of the mechanism of action. Both compounds should be tested clinically in patients with symptoms of depression.     

Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain

3′,5′-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize cAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague–Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. PDE1B, PDE1C, PDE2A, PDE4A, PDE4D, PDE5A, PDE7A, PDE8A, PDE8B, PDE10A, and PDE11A showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of PDE1A, PDE3A, PDE3B, PDE4B, PDE7A, PDE7B, and PDE9A did not change with age. Age-related increases in PDE11A4, PDE8A3, PDE8A4/5, and PDE1C1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in PDE8A3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKIIα, and CaMKIIβ, decreased expression of the transmembrane AMPA regulatory proteins γ2 (a.k.a. stargazin) and γ8, and increased trimethylation of H3K27. Interestingly, expression of PDE11A4, PDE8A4/5, PDE8A3, and PDE1C1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization.     

The gold nanoparticle size and exposure duration effect on the liver and kidney function of rats: In vivo

Nanoparticles (NPs) offer a great possibility for biomedical application, not only to deliver pharmaceutics, but also to be used as novel diagnostic and therapeutic approaches. Currently, there are no data available regarding to what extent the degree of the toxicity and the accumulation of gold nanoparticles (GNPs) are present in in vivo administration. This study aimed to address the GNP size and exposure duration effect on the liver and kidney function of rats: in vivo.MethodsA total of 30 healthy male Wistar-Kyoto rats of the same age (12 weeks old) and weighing 220–240 g of King Saud University colony were used. Animals were randomly divided into groups, two GNP-treated rat groups and one control group (CG). The 50 μl of 10 and 50 nm GNPs was intraperitoneally administered in rats for exposure duration of 3 days. Then, several biochemical parameters such as aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alanine transaminase (ALT), alkaline phosphatase (ALP), urea (UREA) and creatinine (CREA) were evaluated.ResultsIn this study, the AST values increased with the administration of 10 and 50 nm GNPs compared with the control. The AST values significantly increased with 10 nm GNPs compared with 50 nm GNPs and control. The GGT and ALT values decreased with the administration of 10 and 50 nm GNPs compared with the control. The GGT and ALT values significantly decreased with 50 nm GNPs compared with 10 nm GNPs and control. The ALP values significantly decreased with the administration of 10 and 50 nm GNPs compared with the control. The decrease in ALP values with 10 nm GNPs was higher than those compared with 50 nm GNPs. In this study, the levels of UREA and CREA values increased in a non significant manner after the administration of 10 and 50 nm GNPs compared with the control.ConclusionsThis study demonstrates that the increase in the enzymes AST and the decrease in ALP are smaller GNPs (10 nm) size-dependent for exposure duration of 3 days; while the decrease in the enzymes GGT and ALT are bigger GNPs (50 nm) size-dependent. The levels of UREA and CREA values indicated no significant changes with the administration of 10 and 50 nm GNPs for exposure duration of 3 days compared with the control. The administration of 10 and 50 nm GNPs for short exposure duration of 3 days induced only significant variations with some liver enzymes while kidney showed no significant variations. This study suggests that synthesis and metabolism of GNPs as well as the protection of the liver will be more important issues for medical applications of gold-based nanomaterials in future.     

RU486 facilitates or disrupts the sensitization of sexual behaviors by estradiol in the ovariectomized Long–Evans rat: Effect of timecourse

An acute injection of estradiol benzoate (EB) to the ovariectomized (OVX) rat activates low levels of lordosis, and subsequent progesterone (P) administration augments lordosis and recruits a complete pattern of sexual behavior including appetitive behaviors (e.g., hops/darts and solicitations). However, repeated injections of 5 μg or 10 μg EB (but not 2 μg EB), administered every 4 days to sexually-experienced OVX rats results in a behavioral sensitization, such that lordosis quotients (LQs) and appetitive behaviors progressively increase. We have shown that adrenal P does not play a critical role because behavioral sensitization to EB is not prevented by adrenalectomy. Here we tested whether P receptors play a role by examining the effect of chronic administration of the P receptor antagonist RU486 at a dose that reliably inhibits sexual behavior in fully primed OVX rats. Females were treated with EB (5 or 10 μg), and 5 mg RU486 dissolved in 0.4 mL vehicle (VEH; 80% sesame oil, 15% benzyl benzoate, 5% benzyl alcohol) 48 h and 5 h prior to each of 7 tests, respectively, occurring at 4-day intervals in unilevel 4-hole pacing chambers. Control animals were treated with 2, 5, or 10 μg EB + VEH. As expected, sensitization did not occur in females treated with 2 μg EB + VEH, and those females received fewer intromissions and ejaculations than all other groups. RU486 did not prevent the sensitization of LQ, moderate and high lordosis magnitudes (LM2 and LM3) or appetitive sexual behaviors on early tests, and in fact potentiated appetitive behaviors, LQ, LM2 and LM3, consistent with its facilitative actions in females treated with EB-alone, as we and others have reported previously. However, despite the initial facilitation, blocking P receptors by chronic administration of RU486 inhibited the maintenance of behavioral sensitization to EB.     

Intermittent cold-induced hippocampal oxidative stress is associated with changes in the plasma lipid composition and is modifiable by vitamins C and E in old rats

This study primarily investigated the effects of intermittent cold exposure (ICE) on oxidative stress (OS) in the hippocampus(HC) and plasma lipid profile of old male rats. Secondly, it evaluated structural changes in the hippocampus region of the rat’s brain. Thirdly, it attempted an evaluation of the effectiveness of the combined supplement of vitamins C and E in alleviating cold stress in terms of these biochemical parameters. Thirty male rats aged 24 months were divided into groups of five each: control (CON), cold-exposed at 10 °C (C10), cold-exposed at 5 °C (C5), supplemented control (CON+S), and supplemented cold-exposed at either 5 °C (C5+S) or 10 °C (C10+S). The rats were on a daily supplement of vitamin C and vitamin E. Cold exposure lasted 2 h/day for 4 weeks. Rats showed increased levels of hydrogen peroxide (H₂O₂), and thiobarbituric acid reactive substances (TBARS) in the HC at 10 °C with further increase at 5 °C. Cold also induced neuronal loss in the hippocampus with concomitant elevations in total cholesterol (TCH), triglycerides (TG) and low-density lipoproteins (LDL-C) levels, and a depletion in high-density lipoprotein (HDL-C). A notable feature was the hyperglycaemic effects of ICE and depleted levels of vitamins C and E in the hippocampus and plasma while supplementation increased their levels. More importantly, a positive correlation was observed between plasmatic LDL-C, TCH and TG and hippocampal TBARS and H₂O₂ levels. Further, intensity of cold emerged as a significant factor impacting the responses to vitamin C and E supplementation. These results suggest that cold-induced changes in the plasma lipid profile correlate with OS in the hippocampus, and that vitamin C and E together are effective in protecting from metabolic and possible cognitive consequences in the old under cold exposures.     

Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms

Diabetic patients are at increased risk to develop cognitive deficit and senile dementia. This study was planned to assess the benefits of chronic carnosine administration on prevention of learning and memory deterioration in streptozotocin (STZ)-diabetic rats and to explore some of the involved mechanisms. Rats were divided into 5 groups: i.e., control, carnosine100-treated control, diabetic, and carnosine-treated diabetics (50 and 100 mg/kg). Carnosine was injected i.p. at doses of 50 or 100 mg/kg for 7 weeks, started 1 week after induction of diabetes using streptozotocin. Treatment of diabetic rats with carnosine at a dose of 100 mg/kg at the end of the study lowered serum glucose, improved spatial recognition memory in Y maze, improved retention and recall in elevated plus maze, and prevented reduction of step-through latency in passive avoidance task. Furthermore, carnosine at a dose of 100 mg/kg reduced hippocampal acetylcholinesterase (AChE) activity, lowered lipid peroxidation, and improved superoxide dismutase (SOD) activity and non-enzymatic antioxidant defense element glutathione (GSH), but not activity of catalase. Meanwhile, hippocampal level of nuclear factor-kappaB (NF-κB), tumor necrosis factor α (TNF-α), and glial fibrillary acidic protein (GFAP) decreased and level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) increased upon treatment of diabetic group with carnosine at a dose of 100 mg/kg. Taken together, chronic carnosine treatment could ameliorate learning and memory disturbances in STZ-diabetic rats through intonation of NF-κB/Nrf2/HO-1 signaling cascade, attenuation of astrogliosis, possible improvement of cholinergic function, and amelioration of oxidative stress and neuroinflammation.     

Flesinoxan challenge suggests that chronic treatment with paroxetine in rats does not desensitize receptors controlling 5-HT synthesis

It has been proposed that the desensitization of 5-HT_1A (5-hydroxytryptamine; serotonin) receptors following chronic therapy with selective serotonin reuptake inhibitors (SSRIs) is necessary for their therapeutic efficacy. Stimulation of the 5-HT_1A receptors decreases serotonin (5-HT) synthesis and release, but it is not clear if the receptors are fully desensitized following chronic SSRI treatment. The main objective of this study was evaluation of ability of 5-HT_1A receptors to modulate 5-HT synthesis after 14-day paroxetine treatment. 5-HT_1A receptor sensitivity following chronic administration of the SSRI paroxetine was assessed by the ability of an acute challenge with the 5-HT_1A agonist, flesinoxan, to modulate 5-HT synthesis in the rat brain. The rates of 5-HT synthesis were measured using the α-[¹⁴C]methyl-l-tryptophan autoradiographic method. The rats were treated for 2 weeks with paroxetine (10 mg/(kg day), s.c., delivered by osmotic minipump). After this treatment, the rats received an acute challenge with flesinoxan (5 mg/kg, i.p.), while the control rats were injected with the vehicle. Forty minutes following the flesinoxan injection, the tracer, α-[¹⁴C]methyl-l-tryptophan, was injected over 2 min. 5-HT synthesis rates were calculated from autoradiographically measured tissue tracer concentrations and plasma time–activity curves. The results demonstrated that the acute flesinoxan challenge produced a significant decrease in 5-HT synthesis rates throughout the rat brain. The greatest decrease was observed in the ventral hippocampus, somatosensory cortex and the ascending serotonergic cell bodies. In comparison with data reported on an acute challenge with flesinoxan in naïve rats (rats without any other treatment), the results presented here suggest a greater effect of flesinoxan on synthesis reduction in rats chronically treated with paroxetine. The results also suggest that the 5-HT receptors were not fully desensitized by paroxetine treatment, and that the stimulation of 5-HT_1A receptors with an agonist is still capable of reducing 5-HT synthesis.     

Increased melatonin may play dual roles in the striata of a 6-hydroxydopamine model of Parkinson's disease

AimsTo investigate dynamic changes and roles of melatonin (MLT) in the striata of 6-hydroxydopamine (6-OHDA)-treated rats.Main methodsA Parkinson's disease (PD) rat was established by a unilateral injection of 6-OHDA into the right substantia nigra pars compacta (SNc) and the right medial forebrain bundle (MFB) to achieve a complete lesion of the ipsilateral nigrostriatal DA system. Dialysates were collected in the lesioned striatum at different time intervals by in vivo microdialysis. In addition, both contralateral and ipsilateral striatum tissues were collected at two time intervals (10:00 and 22:00 h) at 3 and 6 weeks after lesioning. The levels of DA, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysates, as well as MLT in the dialysates and tissues were determined using HPLC.Key findingsThe dialysate contents of DA, DOPAC and HVA in the lesioned striatum were significantly decreased (P < 0.001) in comparison with those in the controls or in the unlesioned side 3 weeks after lesioning while the extracellular level of MLT in the lesioned striatum in these corresponding time intervals distinctly increased when compared with those in the controls (P < 0.05). The tissue MLT contents increased in the bilateral striata in different degrees at 6 weeks post-lesion (P < 0.05). Moreover, increased MLT levels correlate well with rotations or DA changes in the lesioned striatum.SignificanceThese data suggest that 6-OHDA lesion manipulates the MLT secretion pattern. Increased striatal MLT level by a unilateral intracerebral injection of 6-OHDA may play dual roles in the progression of PD in rats.     

Short-term nicotine exposure induces long-lasting modulation of gustatory plasticity in Caenorhabditis elegans

Nicotine administration induces many effects on animal behavior. In wild-type Caenorhabditis elegans, gustatory plasticity results in reduced chemotaxis toward NaCl of otherwise attractive concentrations after pre-exposure to 100 mM NaCl in the absence of food. However, acute nicotine administration during a 15 min pre-exposure period inhibits gustatory plasticity, whereas chronic nicotine administration during worm development facilitates the plasticity. To investigate the relationship between the duration of nicotine administration and its effects, we exposed worms to nicotine for various periods during development. The modulatory effect of nicotine on gustatory plasticity was gradually switched from inhibition to facilitation with increased duration of nicotine administration. Moreover, inhibition of plasticity was sustained after relatively short-term chronic administration, with effects lasting for 45 h after the removal of nicotine. Similar to the acute inhibitory effect after 15 min nicotine pre-exposure, the inhibitory effect after short-term chronic administration was dependent on the nicotinic acetylcholine receptor subunit genes lev-1 and unc-29, and genes involved in serotonin biosynthesis bas-1 and tph-1. The impaired inhibition in bas-1 and tph-1mutants was recovered by exogenous serotonin, demonstrating that serotonin plays an important role in the long-lasting inhibitory effects of short-term chronic nicotine exposure.     

Adaptation of rat gastric tissue against indomethacin toxicity

Indomethacin is used in the treatment of inflammatory diseases. But the drug toxicity limits its usage. This study investigated whether adaptation occurred after various dosages of repeated (chronic) indomethacin in rats to the gastro-toxic effects of indomethacin. It also examined whether the adaptation was related to oxidant–antioxidant mechanisms and oxidative DNA damage in gastric tissue. To illuminate the adaptation mechanism in the gastric tissue of rats given various dosages of chronic indomethacin, the levels of oxidants and antioxidants (GSH, MDA, NO, SOD and MPO), activities of COX-1 and COX-2 enzymes and oxidative DNA damage (8-OHd Gua/10⁵ Gua) were measured. Results were compared to 25-mg/kg single-dose indomethacin group, and the role of oxidant and antioxidant parameters and oxidative DNA damage in the adaptation mechanism was evaluated. The average ulcer areas of gastric tissue of the 0.5-, 1-, 2-, 3-, 4-, and 5-mg/kg dosages of chronic indomethacin given to rats were 19.5 ± 3.7, 12.5 ± 3.3, 10 ± 5.2, 4.5 ± 3.6, 8.6 ± 2.4, and 9.5 ± 2.1 mm², respectively. This rate was measured as 21.3 ± 2.6 mm² in the single-dose indomethacin group. Consequently, after various dosages of repeated (chronic) indomethacin administration in rats, it was observed that a clear adaptation developed against gastric damage and that gastric damage was reduced. The best adaptation was observed in the gastric tissue of the 3-mg/kg chronic indomethacin group. In parallel with the damage reduction, the oxidant parameters (MDA and MPO) and oxidative DNA damage (8-OHd Gua/10⁵ Gua) were reduced, and the antioxidant parameters (GSH, NO and SOD) were increased. There is no relation between COX enzymes and adaptation mechanism. This circumstance shows that not COX-1 and COX-2 enzymes, oxidant and antioxidant parameters may play a role in the adaptation mechanism.     

Minocycline inhibits 5-lipoxygenase expression and accelerates functional recovery in chronic phase of focal cerebral ischemia in rats

AimsWe previously reported that minocycline attenuates acute brain injury and inflammation after focal cerebral ischemia, and this is partly mediated by inhibition of 5-lipoxygenase (5-LOX) expression. Here, we determined the protective effect of minocycline on chronic ischemic brain injury and its relation with the inhibition of 5-LOX expression after focal cerebral ischemia.Main methodsFocal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion followed by reperfusion for 36 days. Minocycline (45 mg/kg) was administered intraperitoneally 2 h and 12 h after ischemia and then every 12 h for 5 days. Sensorimotor function was evaluated 1–28 days after ischemia and cognitive function was determined 30–35 days after ischemia. Thereafter, infarct volume, neuron density, astrogliosis, and 5-LOX expression in the brain were determined.Key findingsMinocycline accelerated the recovery of sensorimotor and cognitive functions, attenuated the loss of neuron density, and inhibited astrogliosis in the boundary zone around the ischemic core, but did not affect infarct volume. Minocycline significantly inhibited the increased 5-LOX expression in the proliferated astrocytes in the boundary zone, and in the macrophages/microglia in the ischemic core.SignificanceMinocycline accelerates functional recovery in the chronic phase of focal cerebral ischemia, which may be partly associated with the reduction of 5-LOX expression.     

The protective effect of montelukast sodium on carbon tetrachloride induced hepatopathy in rat

AimThis study investigates the effects of montelukast sodium (MK) (CysLTLT1 receptor antagonist) on CCl₄induced hepatopathy on rat.Material and methodsWe worked on 4 groups of 10 Wistar male rats each. The groups received as follows: group I (control group) – saline, group II – MK 5 mg/kg/day i.p. for 5 days, group III – MK 5 mg/kg/day i.p., 1 day prior to and 4 days concomitantly with CCl₄ p.o., 0.3 ml/Kg/day and group IV – CCl₄, p.o., 0.3 ml/Kg/day for 4 days. One day after the last administration, samples of blood were taken and alanine aminotransferase (ALT), total bilirubin (TB), direct bilirubin (DB), malondialdehyde (MDA), catalase (CAT) as well as total antioxidant capacity (TAC) were determined. The histopathological exam was performed. We also determined superoxide dismutase (SOD), MDA, CAT and GSH in liver homogenate.ResultsCompared to group IV, group III exhibited statistically significant lower levels of ALT (318 ± 15.75 versus 203.14 ± 10.28 UI, p < 0.0001), TB (3.16 ± 0.30 versus 1.99 ± 0.08 mg/dl, p < 0.0001), MDA in blood and in liver homogenate (4.98 ± 1.71 versus 2.15 ± 1.18 nmol/ml, p = 0.0004) and higher levels of SOD and CAT. Histopathologically, group IV presented important macro- and micro-vesicular hepatic steatosis and group III preserved lobular histoarchitecture and had less severe cellular lesions.ConclusionMK exhibits a partial hepatoprotective effect on rats treated with CCl₄.     

Effect of acetazolamide on cytokines in rats exposed to high altitude

Acute mountain sickness (AMS) is a dangerous hypoxic illness that can affect humans who rapidly reach a high altitude above 2500 m. In the study, we investigated the changes of cytokines induced by plateau, and the acetazolamide (ACZ) influenced the cytokines in rats exposed to high altitude. Wistar rats were divided into low altitude (Control), high altitude (HA), and high altitude + ACZ (22.33 mg/kg, Bid) (HA + ACZ) group. The rats were acute exposed to high altitude at 4300 m for 3 days. The HA + ACZ group were given ACZ by intragastric administration. The placebo was equal volume saline. The results showed that hypoxia caused the heart, liver and lung damage, compared with the control group. Supplementation with ACZ significantly alleviated hypoxia-caused damage to the main organs. Compared with the HA group, the biochemical and blood gas indicators of the HA + ACZ group showed no difference, while some cytokines have significantly changed, such as activin A, intercellular adhesion molecule-1 (ICAM-1, CD54), interleukin-1α,2 (IL-1α,2), l-selectin, monocyte chemotactic factor (MCP-1), CC chemokines (MIP-3α) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). Then, the significant difference pro-inflammatory cytokines in protein array were chosen for further research. The protein and mRNA content of pro-inflammatory cytokines MCP-1, interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), interferon-γ (IFN-γ) in rat lung were detected. The results demonstrated that the high altitude affected the body’s physiological and biochemical parameters, but, ACZ did not change those parameters of the hypoxia rats. This study found that ACZ could decrease the content of pro-inflammatory cytokines, such as MCP-1, IL-1β, TNF-α and IFN-γ in rat lungs, and, the lung injury in the HA + ACZ group reduced. The mechanism that ACZ protected hypoxia rats might be related to changes in cytokine content. The reducing of the pro-inflammatory cytokines in rat lung might be other reason to explain ACZ against the acute mountain sickness.     

Oral administration of melatonin modulates the expression of tumor necrosis factor-α (TNF-α) gene in irradiated rat cervical spinal cord

AimWe aimed to determine the changes in TNF-α expression and Malondialdehyde (MDA) level in a short time after irradiation. Furthermore, we evaluated the effect of melatonin on the modulation of TNF-α gene expression.BackgroundThe radio-sensitivity of the cervical spinal cord limits the dose of radiation which can be delivered to tumors in the neck region. There is increasing evidence that TNF-α has a role in the development of the acute phase of spinal cord injury.Materials/MethodsFour groups of rats were investigated. Group 1 (vehicle treatment) served as the control. Group 2 (radiation) was treated with the vehicle, and 30 min later, the rats were exposed to radiation. Group 3 (radiation + melatonin) was given an oral administration of melatonin (100 mg/kg body weight) and 30 min later exposed to radiation in the same manner as in group 2. Group 4 (melatonin-only) was also given an oral administration of melatonin (100 mg/kg body weight). 5 mg/kg of melatonin was administered daily to rats in groups 3 and 4, and the vehicle was administered daily to rats in groups 1 and 2.ResultsThree weeks after irradiation, TNF-α gene up-regulated almost 5 fold in the irradiated group compared to the normal group. TNF-α gene expression in the melatonin pretreatment group, compared to the radiation group, was significantly down-regulated 3 weeks after irradiation (p < 0.05). MDA levels increased after irradiation and then significantly decreased under melatonin treatment.ConclusionWe suggest that inhibition of TNF-α expression by oral administration of melatonin may be a therapeutic option for preventing radiation-induced spinal cord injury.     

Effect of separate and combined exposure of selenium and diazinon on rat sperm motility by computer assisted semen analysis

Effects of selenium (Se) and diazinon (DZN) on sperm motility parameters in rats were investigated. Male rats received a separate dose of Se (2 mg kg⁻¹ b.w., intraperitoneally, 5 mg L⁻¹, per os in drinking water), diazinon (20 mg kg⁻¹ b.w., intraperitoneally, 40 mg L⁻¹, per os in drinking water), and in combination (Se + DZN) with the same dosage as in the separate administration. 36 h an intraperitoneal (i.p.) and after 90 days of per oral (p.o.) exposure, thirteen parameters of sperm motility were evaluated using a Computer Assisted Sperm Analyzer (CASA). Almost all the evaluated sperm motility parameters significantly decreased in Se p.o. exposed groups. In the Se i.p. group decrease was noted only in beat cross frequency (BCF) and progressive motility. Significant decline in the sperm motility, progressive motility, BCF and increase in amplitude of lateral head displacement (ALH) were recorded after DZN i.p. administration. In DZN p.o. group, significant increase in ALH, velocity average path (VAP) and curvilinear velocity (VCL) but decrease in progressive motility and BCF was detected. Se + DZN i.p. administration caused a significant decrease in motility, progressive motility and BCF. Per oral administration of Se + DZN decreased all motility parameters except LIN, WOB and ALH. Sperm abnormalities increased in all experimental conditions. Se and DZN negatively affected sperm structure and function in separate doses or in combination. No protective effect of Se was observed.