Zhi-Qiang Zhou

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test

Abstract Introduction. Previous studies have shown that a single sub-anesthetic dose of ketamine exerts fast-acting antidepressant effects in patients and in animal models of depression. However, the underlying mechanisms are not totally understood. This study aims to investigate the effects of acute administration of different doses of ketamine on the immobility time of rats in the forced swimming test (FST) and to determine levels of hippocampal brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). Methods. Forty male Wistar rats weighing 180–220 g were randomly divided into four groups (n = 10 each): group saline and groups ketamine 5, 10, and 15 mg/kg. On the first day, all animals were forced to swim for 15 min. On the second day ketamine (5, 10, and 15 mg/kg, respectively) was given intraperitoneally, at 30 min before the second episode of the forced swimming test. Immobility times of the rats during the forced swimming test were recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and mTOR levels. Results. Compared with group saline, administration of ketamine at a dose of 5, 10, and 15 mg/kg decreased the duration of immobility (P < 0.05 for all doses). Ketamine at doses of both 10 and 15 mg/kg showed a significant increase in the expression of hippocampal BDNF (P < 0.05 for both doses). Ketamine given at doses of 5, 10, and 15 mg/kg showed significant increases in relative levels of hippocampal p-mTOR (P < 0.05 for all doses) Conclusion. The antidepressant effect of ketamine might be related to the increased expression of BDNF and mTOR in the hippocampus of rats.

Acute Increases in Plasma Mammalian Target of Rapamycin, Glycogen Synthase Kinase-3β, and Eukaryotic Elongation Factor 2 Phosphorylation After Ketamine Treatment in Three Depressed Patients

To the Editor: R ecently, an increasing number of studies have shown that ketamine has a definite antidepressant effect for patients with depression (1,2). Unlike traditional antidepressants, ketmine exerts its antidepressant effect with a rapid onset of action ithin 1 to 2 hours (3). Unfortunately, the mechanisms underlying his compelling therapeutic effect of ketamine are still not fully lucidated. An innovative research conducted by Li et al. (4) has demontrated that mammalian target of rapamycin (mTOR)-dependent ynapse formation in rat prefrontal cortex is involved in the mechnisms of ketamine’s fast-acting antidepressant effect, which is onfirmed by a subsequent study that ketamine produces its antiepressant effect with a continued increase of the mTOR phosphorlation from baseline to 100 min in peripheral mononuclear cells fter the initiation of ketamine infusion in a depressed patient (5). owever, Autry and colleagues (6) have observed a decrease in the evel of eukaryotic elongation factor 2 phosphorylation (p-eEF2) ut without a significant change in the expression of mTOR in rat ippocampus after the ketamine administration. Currently, Burel et l. (7) have found that an increasing inhibitory phosphorylation of lycogen synthase kinase-3 (p-GSK-3) is essential for the fast-acting ntidepressant effect of ketamine. Collectively, these findings sugest that mTOR, GSK-3 , and eEF2 are implicated in the underlying echanisms of the fast-acting antidepressant effect of ketamine. owever, there is no study reporting the changes of GSK-3 and EF2 expression after the clinical use of ketamine. Therefore, the resent study aimed to determine the expression of GSK-3 and EF2 for the first time and to investigate further the expression of TOR in peripheral blood plasma after the ketamine treatment in epressed patients. The present study was approved by the Ethics Committee of inling Hospital. Three male patients aged 22, 19, and 31 met DSMV-TR criteria for major depressive disorder without psychotic feaures and were involved in this clinical study. They had not had lcohol or substance abuse or dependence within the previous 3 onths. All patients were in good physical health with no unstable edical conditions, as determined by medical history, physical exmination, electrocardiogram, chest X-ray, routine blood labs, and rinalysis. They did not receive any antidepressant treatment be-

Inhibition of the L-arginine-nitric oxide pathway mediates the antidepressant effects of ketamine in rats in the forced swimming test.

Converging evidence shows that the acute administration of a sub-anaesthetic dose ketamine produces fast-acting and robust antidepressant properties in patients suffering from major depressive disorder. However, the underlying mechanisms have not been fully elucidated. The present study aimed to investigate the role of the L-arginine-nitric oxide pathway in the antidepressant effects of ketamine in rats performing the forced swimming test (FST). Ketamine (10 mg/kg) significantly decreased immobility times in the FST and the activities of total nitric oxide synthases (T-NOS), inducible NOS (iNOS), and endothelial NOS (eNOS) in the rat hippocampus. Interestingly, the plasma activities of T-NOS, iNOS, and eNOS increased after administration of ketamine. Furthermore, the activities of neuronal NOS (nNOS) did not change significantly in either the hippocampus or plasma after ketamine administration. The antidepressant effects of ketamine were prevented by pre-treatment with l-arginine (750 mg/kg). Pre-treatment with the NOS inhibitor L-NG-nitroarginine methyl ester at a sub-antidepressant dose of 50 mg/kg and ketamine at a sub-antidepressant dose of 3 mg/kg reduced immobility time in the FST compared to treatment with either drug alone. None of the drugs affected crossing and rearing scores in the open field test. These results suggest that the L-arginine-nitric oxide pathway is involved in the antidepressant effects of ketamine observed in rats in the FST and this involvement is characterised by the inhibition of brain T-NOS, iNOS, and eNOS activities.

Hydroxyethyl starch exhibits antiinflammatory effects in the intestines of endotoxemic rats.

We performed the present in vivo study to investigate the effect of hydroxyethyl starch (HES) on intestinal production of inflammatory mediators and activation of transcription factors during endotoxemia. Rats with endotoxemia induced by lipopolysaccharide (LPS) (5 mg/kg, IV) were treated with HES (16 mL/kg, IV) or saline (64 mL/kg, IV). At 2, 3, or 6 h after the LPS challenge, the rat ileal tissues were collected. Various ileal inflammatory mediator levels (tumor necrosis factor-α, interleukin [IL]-6, cytokine-induced neutrophil chemoattractant-1, and IL-10), inflammatory mediator messenger RNAs (mRNAs), activities of nuclear factor (NF)-&kgr;B and activator protein (AP)-1, and ileal myeloperoxidase-positive cells were determined in each group. HES significantly reduced the increased intestinal levels of tumor necrosis factor-α, IL-6, cytokine-induced neutrophil chemoattractant-1, and the mRNAs in the endotoxemic rats. Similarly, HES could decrease the myeloperoxidase-positive cells induced by LPS and also inhibit ileal NF-&kgr;B and AP-1 activations. Our results suggest that during endotoxemia HES may down-regulate intestinal inflammatory mediator production, and this antiinflammatory effect of HES may act through suppression of NF-&kgr;B and AP-1 activations.

Akt Mediates GSK-3β Phosphorylation in the Rat Prefrontal Cortex during the Process of Ketamine Exerting Rapid Antidepressant Actions

Ketamine may produce rapid and sustained antidepressant effects. Despite the fact that the detailed underlying mechanism remains unknown, recent studies have suggested the involvement of the mammalian target of rapamycin (mTOR) pathway and glycogen synthase kinase-3 (GSK-3) signal, respectively, in the process of ketamine exerting antidepressant actions. This study aimed to investigate the mechanism by which ketamine phosphorylates GSK-3β in the rat prefrontal cortex (PFC) via applying vehicle or the antagonists of mTOR signalling pathway proteins including PI3K/Akt, mTOR and p70S6 kinase to the rats in the forced swimming test (FST) prior to ketamine administration, and subsequently observing the levels of phosphorylated GSK-3β, mTOR and p70S6K in rat PFC as well as the immobility time of rats in the FST. Our results revealed that compared to treatment with vehicle, ketamine increased the levels of phosphorylated GSK-3β in rat PFC (p < 0.05), which was attenuated by PI3K/Akt antagonist pretreatment (p < 0.05), but could not be affected by mTOR antagonist or p70S6K antagonist pretreatment. In addition, all the antagonists reversed the ketamine-induced increases in the phosphorylation of mTOR and p70S6K (p < 0.05). They also all abolished the rapid-acting antidepressant actions of ketamine demonstrated by the increased immobility time of rats in the FST. In conclusion, Akt mediates the phosphorylation of GSK-3β in rat PFC during the process of ketamine exerting rapid antidepressant actions.

Tramadol pretreatment enhances ketamine-induced antidepressant effects and increases mammalian target of rapamycin in rat hippocampus and prefrontal cortex.

Several lines of evidence have demonstrated that acute administration of ketamine elicits fast-acting antidepressant effects. Moreover, tramadol also has potential antidepressant effects. The aim of this study was to investigate the effects of pretreatment with tramadol on ketamine-induced antidepressant activity and was to determine the expression of mammalian target of rapamycin (mTOR) in rat hippocampus and prefrontal cortex. Rats were intraperitoneally administrated with ketamine at the dose of 10 mg/kg or saline 1 h before the second episode of the forced swimming test (FST). Tramadol or saline was intraperitoneally pretreated 30 min before the former administration of ketamine or saline. The locomotor activity and the immobility time of FST were both measured. After that, rats were sacrificed to determine the expression of mTOR in hippocampus and prefrontal cortex. Tramadol at the dose of 5 mg/kg administrated alone did not elicit the antidepressant effects. More importantly, pretreatment with tramadol enhanced the ketamine-induced antidepressant effects and upregulated the expression of mTOR in rat hippocampus and prefrontal cortex. Pretreatment with tramadol enhances the ketamine-induced antidepressant effects, which is associated with the increased expression of mTOR in rat hippocampus and prefrontal cortex.

Ketamine inhibits LPS-induced calcium elevation and NF-kappa B activation in monocytes

AbstractObjective:To investigate whether ketamine could inhibit lipopolysaccharide (LPS)-induced intracellular calcium elevation and NF-kappa B activation in monocytes. Materials and methods:Isolated rat monocytes were challenged with 10 μg/ml LPS with or without the presence of various concentrations of ketamine (10, 100, 1000 μM). Intracellular calcium was monitored by laser confocal microscopy. NF-kappa B activity of the nuclear extracts of monocytes was analyzed by electrophoretic mobility shift assay (EMSA). Results:LPS provoked a significant calcium elevation and enhanced NF-kappa B activity in monocytes. Ketamine above concentration of 100 μM inhibited endotoxin-induced intracellular calcium elevation and NF-kappa B activity. Ketamine itself had no effect on either of them. Conclusions:These findings suggest that ketamine could suppress NF-kappa B in monocytes exposed to endotoxin, and this anti-inflammatory effect might act through attenuating intracellular calcium elevation.

Lighter General Anesthesia Causes Less Decrease in Arterial Pressure Induced by Epinephrine Scalp Infiltration During Neurosurgery

Scalp infiltration with epinephrine-containing lidocaine solution can elicit significant hypotension before craniotomy under general anesthesia. A prospective randomized controlled study was designed to observe whether a lighter depth of general anesthesia could prevent the unintentional hypotension induced by the epinephrine scalp infiltration during neurosurgery or not. Fifty patients undergoing scheduled neurosurgery involving craniotomy were randomly allocated into 2 groups. After anesthesia induction, anesthesia was maintained with propofol 2 μg/mL and rimifentanil 2 ng/mL by target-controlled infusion in group 1, and propofol 4 μg/mL and rimifentanil 4 ng/mL in group 2 (control group), respectively. All the patients received epinephrine scalp infiltration with 1% lidocaine 16 mL containing epinephrine 5 μg/mL. Mean arterial pressure (MAP) and heart rate were recorded at 30-second interval from the baseline to 5 minutes after the beginning of local infiltration. Bispectral index readings indicated group 1 had the lighter general anesthesia than group 2 (P<0.05). MAP was higher (P<0.05) and heart rate was lower (P<0.05) at 1.5 minutes time point in group 1 than group 2. The mean percentage of maximal decrease in MAP was group 1 (13%) group 2 (4%) without significant difference (P>0.05). The results implied that keeping a lighter general anesthesia caused less decrease in arterial blood pressure and was a relative effective method to prevent hypotension episode induced by epinephrine scalp infiltration.

Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus

Ketamine exerts rapid and robust antidepressant properties in both animal models and depressed patients and tramadol possesses potential antidepressant effects. Brain-derived neurotrophic factor (BDNF) is an important biomarker for mood disorders and tropomyosin-related kinase B (TrkB) is a high affinity catalytic receptor for BDNF.We hypothesized that tramadol pretreatment might reinforce ketamine-elicited antidepressant effects with significant changes in hippocampal BDNF and TrkB levels in rats. Immobility time of rats receiving different treatment in the forced swimming test (FST) was observed. Levels of BDNF and TrkB in hippocampus were measured by enzyme linked immunosorbent assay. Results showed that tramadol (5 mg/kg) administrated alone neither elicited antidepressant effects nor altered BDNF or TrkB level. However, pretreatment with tramadol (5 mg/kg) enhanced the ketamine (10 mg/kg) -elicited antidepressant effects and upregulated the BDNF and TrkB levels in hippocampus. In conclusion, tramadol pretreatment reinforces the ketamine-elicited antidepressant effects, which is associated with the increased levels of BDNF and TrkB in rat hippocampus.

Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model

Although ketamine shows a rapid and sustained antidepressant effect, the precise mechanisms underlying its effect are unknown. Recent studies indicate a key role of p11 (also known as S100A10) in depression-like behavior in rodents. The present study aimed to investigate the role of p11 in the antidepressant-like action of ketamine in chronic unpredictable mild stress (CUMS) rat model. The open-field test, forced swimming test and sucrose preference test were performed after administration of ketamine (10 mg kg−1) or a combination of ketamine and ANA-12 (a tropomyosin-related kinase B (TrkB) antagonist; 0.5 mg kg−1). The lentivirus vector for p11 was constructed to knock down the hippocampal expression of p11. In the CUMS rats, ketamine showed a rapid (0.5 h) and sustained (72 h) antidepressant effect, and its effect was significantly blocked by co-administration of ANA-12. Furthermore, ketamine significantly increased the reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of CUMS rats, whereas ketamine did not affect the expression of p11 in CUMS rats 0.5 h after administration. In addition, ketamine significantly increased the reduced ratio of p-TrkB/TrkB in the hippocampus by CUMS rats, and its effect was also blocked by ANA-12. Moreover, the reduced expression of BDNF and p11 in the hippocampus of CUMS rats was significantly recovered to control levels 72 h after ketamine administration. Interestingly, knockdown of hippocampal p11 caused increased immobility time and decreased sucrose preference, which were not improved by ketamine administration. These results suggest that p11 in the hippocampus may have a key role in the sustained antidepressant effect of ketamine in the CUMS model of depression.