Potential of levetiracetam in mood disorders: a preliminary review

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.     

Altered growth patterns of colorectal liver metastases after thermal ablation

BACKGROUND: Thermal ablation by radiofrequency or laser is used increasingly for the treatment of colorectal liver metastases. Recurrence after thermal ablation is common and occurs both locally and at distant sites. One possible cause of this recurrence may be a result of growth stimulation of micrometastases in the remaining liver. This study examined the impact of thermal ablation on growth patterns of hepatic micrometastases. METHODS: Colorectal liver metastases were induced in male CBA-strain mice via an intrasplenic injection of a murine-derived cancer cell line. Subtotal thermal ablation of the left posterior lobe of the liver (30% of total liver volume) was performed by neodymium yttrium-aluminum-garnet laser 7 days after induction of metastases. The distribution, number, cross-sectional diameter, volume, and proliferation rate of established neoplasms were compared with controls at 21 days after tumor induction. The effect of thermal ablation of 7% of the total liver volume by laser on the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor 2 (FGF-2), transforming growth factor beta, and cellular proliferation (Ki-67 antigen) adjacent to the ablated site was assessed by immunohistochemistry in separate groups of animals at specific time points after therapy. RESULTS: Thermal ablation did not alter the overall volume, number, size, and proliferation rate of neoplasms 21 days after laser ablation. There were no extrahepatic metastases after therapy. The number of neoplasms in the regenerated posterior lobe was equivalent to control despite subtotal ablation (29 +/- 2 vs 27 +/- 2; P = NS). A greater amount of metastases occupied the regenerated thermal-ablated lobe compared with controls (55% +/- 4% vs 29% +/- 3%; P < .04). Thermal ablation stimulated liver proliferation adjacent to the treatment site at 12 hours compared with untreated controls. Stimulation peaked at 72 hours (20% +/- 1% vs 1% +/- 1%; P < .001) and persisted to 21 days after therapy. FGF-2 and VEGF expression increased in liver tissue adjacent to the ablation site compared with baseline, peaking at 12 hours (112% +/- 2% vs 102% +/- 1%; P < .001) and 72 hours (114% +/- 2% vs 101% +/- 1%; P < .001), respectively. CONCLUSIONS: Thermal ablation promotes the progression of micrometastases to form macroscopically detectable neoplasms in treated regenerating liver. This effect may relate to an increased expression of VEGF and FGF-2 adjacent to the treatment site.     

Ncm-D-aspartate: a novel caged D-aspartate suitable for activation of glutamate transporters and N-methyl-D-aspartate (NMDA) receptors in brain tissue

The D-isomer of aspartate is both a substrate for glutamate transporters and an agonist of N-methyl-D-aspartate (NMDA) receptors. To monitor the behavior of these receptors and transporters in intact tissue we synthesized a new photo-labile analogue of D-aspartate, N-[(6-nitrocoumarin-7-yl)methyl]-D-aspartic acid (Ncm-D-aspartate). This compound was photolyzed rapidly (t(1/2)=0.11 micros) by UV light with a quantum efficiency of 0.041 at pH 7.4. In acute hippocampal slices, photolysis of Ncm-D-aspartate by brief (1 ms) exposure to UV light elicited rapidly activating inward currents in astrocytes that were sensitive to inhibition by the glutamate transporter antagonist DL-threo-beta-benzyloxyaspartic acid (TBOA). Neither Ncm-D-aspartate nor the photo-released caging group exhibited agonist or antagonist activity at glutamate transporters, and Ncm-D-aspartate did not induce transporter currents prior to photolysis. Glutamate transporter currents were also elicited in cerebellar Purkinje cells in response to photolysis of Ncm-D-aspartate. Photo-release of D-aspartate from Ncm-D-aspartate did not induce alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor or metabotropic glutamate receptor (mGluR) currents, but triggered robust NMDA receptor currents in neurons; Ncm-D-aspartate and the photolzyed caging group were similarly inert at NMDA receptors. These results indicate that Ncm-D-aspartate can be used to study NMDA receptors at excitatory synapses and interactions between transporters and receptors in brain tissue.     

The effect of hyperbaric oxygen on apoptosis and proliferation in severe acute pancreatitis

Objectives:

This paper investigates the significance of apoptosis in severe acute pancreatitis (SAP) and the possible modulating effects of hyperbaric oxygen (HBO).

Methods:

Wistar rats (250–350 g) were induced with SAP by biliopancreatic infusion of 4% sodium taurocholate. Rats were randomized for HBO treatment. Pancreatic tissue was stained for apoptosis with immunohistochemistry (anti-CASPASE-3 antibody and TUNEL), and histopathology haematoxylin and eosin (H&E). Acini were stained for proliferation with an anti-KI67 antibody. ImageProPlus was used to quantify apoptosis and proliferation in acinar cells. Statistical analysis was performed with two-independent-sample t-test or non-parametric Mann–Whitney test.

Results:

In normal acini there is a low rate of apoptosis (0.165 ± 0.157%, 0.181 ± 0.168%, 0.130 ± 0.298% in CASPASE-3, H&E and TUNEL, respectively) and proliferation (0.951 ± 0.926%) (mean ± standard deviation [SD]). When compared with normal, apoptosis (CASPASE-3: 1.28 ± 1.12%, P= 0.008; 2.40 ± 3.04%, P= 0.101; 1.23 ± 0.87%, P= 0.091; H&E: 0.47 ± 0.36%, P= 0.051; 0.69 ± 0.63%, P= 0.001; 0.68 ± 0.28%, P= 0; TUNEL: 1.08 ± 1.42%, P= 0; 1.96 ± 1.87%, P= 0; 2.36 ± 2.26%, P= 0) and proliferation (1.96 ± 1.89%, P= 0.187; 1.73 ± 1.76%, P= 0.165; 1.36 ± 1.40%, P= 0.571) were increased on days 1, 2 and 3 post-induction, respectively. In comparison with the untreated controls, HBO increased apoptosis on day 1 (CASPASE-3: 3.11 ± 1.97%, P= 0.04; H&E: 0.97 ± 0.76%, P= 0.005) and day 2 (TUNEL: 3.61 ± 3.05%, P= 0.034). Treatment with HBO increased proliferation (3.04 ± 3.14%, P= 0.519; 7.33 ± 7.55%, P= 0.153) on days 2 and 3, respectively, compared with the untreated controls.

Conclusions:

During SAP, acini apoptosis and proliferation were increased. Hyperbaric oxygen therapy may improve the condition of SAP by promoting apoptosis and proliferation.     

A novel 5-HT2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT_2A) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [α] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT_2A receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25-4 mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14 days) treatment with BIP-1 (1 and 2 mg/kg) or amitriptyline (10 mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7 days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT_2A receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT_2A receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.     

Effect of interstitial laser hyperthermia in a murine model of colorectal liver metastases

Interstitial laser hyperthermia (ILH) is an in situ ablative technique used for the treatment of colorectal liver metastases. At present, few data exist concerning the optimum power settings required to maximize tissue necrosis.The aim of this study was to establish the dose-response relationship between the laser power setting and the extent of tissue necrosis produced in liver and tumor tissue, as well as the pattern of necrosis in a murine model of liver metastases. An intrasplenic induction model of liver metastases in 4- to 6-week-old male inbred CBA mice was used. Laser hyperthermia was applied to liver and tumor tissue using a bare optical quartz fiber from a Laserex SLY500 Nd:YAG surgical laser generator. Two-watt and 5-watt power settings were used at specific time intervals. The livers were then excised, fixed in formalin, and the extent and degree of necrosis were measured. Results were expressed as mean ? standard deviation and were normally distributed. Analysis of variance was performed, and the least significant difference was used for post hoc tests. A P value of less than 0.05 was considered significant. Interstitial laser hyperthermia at 5 watts of power produced larger diameters of necrosis than did 2 watts for specific exposure times in normal liver tissue. However, when the total energy applied was compared, there was no significant difference in the diameters of tissue necrosis produced by the two power settings. The diameter of tissue necrosis in the normal liver increased from 2 mm at 10 joules to 8 mm at 600 joules of energy. Within tumor tissue, ILH at 2 and 5 watts produced similar diameters of necrosis for specific exposure times. When amounts of total energy applied were compared, ILH at the lower power setting (2 watts) produced a significantly larger diameter of necrosis than the higher power setting (5 watts). The diameter of necrosis achieved in tumor tissue was significantly larger than that in normal liver tissue at both power settings, for an equivalent amount of applied energy. The difference was more pronounced when ILH was performed at the lower power setting. The maximum diameter of necrosis achieved was 6.8 ± 0.7 mm in normal liver tissue and 7.7 ± 0.8 mm in tumor tissue. Charring of the fiber tip was delayed when the lower power setting was used, occurring after 20 seconds of exposure, compared to 5 seconds at the higher power setting. Similarly, cavitation occurred initially at 50 seconds at 5 watts of power and was delayed until 90 seconds of exposure at 2 watts of power. Histopathologic findings revealed an elliptical area of homogeneous necrosis, with a central acellular coagulum surrounded by intact but nonviable tissue. ILH is capable of producing highly reproducible, uniform, and complete tissue necrosis. The diameter of necrosis is related to the total energy applied. At low-power settings at any given amount of applied energy, a significantly larger diameter of tissue necrosis was achieved in tumor tissue compared to normal liver tissue.     

Metal Contamination in Select Species of Birds in Nilgiris District,Tamil Nadu,India

Variation in metal contamination in six species of birds, namely the Cormorant (Phalacrocorax carbo), Cattle Egret (Bubulcus ibis), Little Egret (Egretta garzetta), Pond Heron (Ardeola grayii), Common Myna (Acridotheres tristis) and Jungle Babbler (Turdoides striatus) in Nilgiris district, Tamil Nadu, India. The accumulation of heavy metals differed among the species studied. On an average, Little Egret accumulated high concentrations of copper (53.31 ± 23.19 ppm) followed by Cattle Egret (16.27 ± 9.83 ppm) in liver. Of all the species, Jungle Babbler recorded the maximum concentrations (20.59 ± 9.07 ppm) in muscle. The Pond Heron recorded the maximum concentration (35.38 ± 11.14 ppm) in brain. On an average the maximum level was in the kidney of Common Myna (7.76 ± 1.80 ppm).