A randomized,double-blind, 6-week,dose-ranging study of pregabalin in patients with restless legs syndrome

ObjectiveThis study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).MethodsThis six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (E_max) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.ResultsThe separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED₅₀) and 90% (ED₉₀) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.ConclusionsIn this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.     

Ketamine-xylazine anaesthesia and orofacial administration of substance P: A lethal combination in rats

Background and aimsKetamine+xylazine mixture is a widely used anaesthetic in animal experiments. In rats anaesthetized with this mixture, we have shown that injection of carrageenan, a standard proinflammatory stimulus, into the cheek (intra-oral injection) induced oedema. A likely mediator of this oedema is substance P (SP), a major transmitter of sensory nerves in orofacial tissue. We have assessed the effects of intra-oral injection of SP in rats.Experimental approachSP (50–1 μg per rat) was injected intra-orally in male adult Holtzman or Wistar rats, anaesthetized with ketamine+xylazine. For comparison, histamine (50 μg) and 5-HT (5 μg) were similarly injected. Antagonists of SP (SR140333, 2 mg/kg), of histamine (pyrilamine, 2 mg/kg) or of 5-HT (pizotifen, 2 mg/kg) were subcutaneously (s.c.) injected, 30 min before the corresponding agonist. Oedema in the cheek was assessed by measuring tissue thickness with calipers.ResultsIntra-oral injection of SP (1–50 μg per rat) in Holtzman or Wistar rats anaesthetized with ketamine+xylazine induced, dose-dependently, death within 15 min, accompanied by signs of excessive salivation. Rats pretreated with SR140333 were protected against SP-induced lethality and the excessive salivation. However, intra-oral injection of either histamine or 5-HT did not induce death, only a characteristic cheek oedema. These doses of SP injected into the hindpaws of conscious Holtzman and Wistar rats only induced oedema with no deaths. In rats anaesthetized with inhaled isoflurane, intra-oral SP (50 μg) induced only cheek oedema, with no deaths or excessive salivation. This oedema was prevented by pre-treating rats with SR140333, pyrilamine and pizotifen.ConclusionIt is likely that the deaths were due to excessive salivation induced by the particular combination of ketamine and SP. Our results are presented as a warning to other experimenters who might use these two otherwise non-toxic conditions and the consequent unexpected and needless loss of experimental animals.     

Combinational effects of ketamine and amphetamine on behaviors and neurotransmitter systems of mice

The combined ingestion of ketamine (Ket) and amphetamine (Amph) by drug-users has been rampant and produced more severe behavioral abnormality. However, the interactive consequences of the two drugs are still unclear. In this study, we treated adult male mice with a single i.p. injection of saline, Amph (5 mg/kg), low Ket (LK, 10 mg/kg), high Ket (HK, 50 mg/kg), or Amph and LK or HK (ALK or AHK) and examined their behavioral and neurochemical changes at 0.5 and 2 h post-injection. Compared with saline, Amph, LK or HK treatment alone increased the levels of motor activities such as locomotion, stereotypy or ataxia of mice. Notably, at combined treatments, LK and HK differentially exacerbated Amph-induced locomotion and stereotypy, whereas Amph worsened LK or HK-produced ataxia. The higher striatal dopamine levels of A, ALK and AHK groups correlated with their greater motor activities. The prolonged increase of dopamine in the motor cortex of ALK and AHK mice may associate with the longer duration of behavioral hyperactivity and greater peak score of locomotion; the greater dopamine level in the somatosensory cortex probably contributes to the more severe ataxia. Furthermore, in the striatum of all drug-treated groups, the expression of GAD₆₇ mRNA and GAD₆₇-positive punctates was higher than respective saline controls, indicating the involvement of GABAergic system in the drug-induced behavioral changes. Our results demonstrate the acute interplay between Amph and Ket in both behavioral and neurochemical aspects for the first time. Dopaminergic and GABAergic systems were affected differentially by the drugs in the striatum.     

Neuroprotective effects of edaravone,a free radical scavenger,on the rat hippocampus after pilocarpine-induced status epilepticus

PurposeEdaravone (MCI-186) is a newly developed antioxidative radical scavenger for the treatment of acute cerebral infarction, exerting neuroprotective effects against ischemic insult. The neuroprotective effects of edaravone on pilocarpine-induced seizures in rats were investigated.MethodsRats were treated intraperitoneally with saline or edaravone (1–30 mg/kg), applied 30 min before pilocarpine hydrochloride (330 mg/kg). The onset of status epilepticus (SE) and mortality were recorded for a period of at least 3 days. The cell loss and immunoreactivities of nitric oxide synthase (NOS) in the hippocampus from control and the day 3 rats after SE, treated with saline or edaravone, were evaluated.ResultsEdaravone (1 mg/kg) significantly prevented cell loss in the hippocampus after SE while easier inducing SE. The higher dose of drug could not induce SE significantly but tended to increase the rate of mortality. Inducible NOS (iNOS) expression was significantly decreased in the hippocampus from day 3 rats treated with 1 mg/kg edaravone, compared with saline group, while neuronal NOS (nNOS) and iNOS significantly increased in the hippocampus treated with saline, compared with control group. Significant alteration of endothelial NOS (eNOS) expression in the hippocampus among control group, saline group, and edaravone group was not shown.ConclusionsEdaravone may act as a neuroprotector for the hippocampus after SE by reducing at least iNOS although the low dose of drug easier induces SE because of preventing an endogenous antiepileptic effect of NO.     

The effect of minocycline on seizures induced by amygdala kindling in rats

PurposeMinocycline is known as a chemical with neuroprotective, anti-inflammatory, and antimicrobial properties. In this study, the effects of minocycline on seizures induced by amygdala kindling in rats were studied.MethodsKindled Wistar rats were injected intraperitoneally with saline and, on the following day, with minocycline (50, 25, and 12.5 mg/kg for the three groups (1–3), respectively). The animals in groups 1–3 had similar protocols. Groups 4 and 5 were given for the rotarod test and received 25 or 50 mg/kg minocycline, respectively, without any kindling stimulation. The animals in groups 6 and 7 (seven each) received 25 mg/kg minocycline or saline, respectively. All the injections were carried out 1 h before kindling stimulation. Seizure parameters, including after discharge duration (ADD), stage 4 latency (S₄L), stage 5 duration (S₅D), and seizure duration (SD), were recorded and compared with those of the saline groups.ResultsMinocycline (50 mg/kg) significantly reduced ADD, 1/S₄L, S₅D, and SD (P < 0.001, P < 0.05, P < 0.001, and P < 0.001, respectively) in group 1. While the administration of 25 mg/kg of minocycline decreased the ADD and S₅D (P < 0.05), in group 2. The injection of 12.5 mg/kg resulted in decreased S₅D (P < 0.001) in group 3. The daily injection of minocycline (25 mg/kg) significantly decreased ADD, S₅D, and SD (P < 0.001) in group 6.ConclusionThe obtained results revealed that minocycline has anticonvulsant effect on seizures induced by amygdala kindling. Thus, it may be useful for epilepsy treatment.     

Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazol-induced seizures in rats

ObjectiveDocosahexaenoic acid (DHA), an omega-3 fatty acid, has been reported to raise seizure thresholds. The purpose of the present study was to test the acute anticonvulsant effects of unesterified DHA in rats, using the maximal pentylenetetrazol (PTZ) seizure model, and also to examine DHA incorporation and distribution into blood serum total lipids and brain phospholipids and unesterified fatty acids. Sedation was measured to monitor for the potential toxicity of DHA.MethodsMale Wistar rats received subcutaneous injections of saline, oleic acid (OA), or DHA. An initial pilot study (Experiment 1) established 400 mg/kg as an effective dose of DHA in the maximal PTZ seizure test. A subsequent time–response study, using 400 mg/kg (Experiment 2), established 1 hour as an effective postinjection interval for administering DHA subcutaneously. A final study (Experiment 3) comprised two different groups. The first group (“seizure-tested rats”) received saline, OA, or DHA (400 mg/kg) subcutaneously, and were seizure tested in the maximal PTZ test 1 hour later to confirm the seizure latency measurements at that time. The second group (“assay rats”) received identical subcutaneous injections of saline, OA, or DHA (400 mg/kg). One hour postinjection, however, they were sacrificed for assay rather than being seizure tested. Assays involved the analysis of serum and brain DHA. Sedation was measured in both Experiment 3 groups during the 1-hour period prior to seizure testing or sacrifice.ResultsAs noted above, 400 mg/kg proved to be an effective subcutaneous dose of DHA (Experiment 1), and 1 hour proved to be the most effective injection–test interval (Experiment 2). In Experiment 3, in the seizure-tested animals, subcutaneous administration of 400 mg/kg of DHA significantly increased latency to PTZ seizure onset 1 hour postinjection relative to the saline- and OA-injected controls, which did not differ significantly from each other (P > 0.05). In the assay animals, no significant effects of treatment on blood serum total lipids or on brain phospholipid or unesterified fatty acid profiles (P > 0.05) were observed. There were also no differences in sedation among the three groups (P > 0.05).ConclusionDHA increases resistance to PTZ-induced seizures without altering measures of sedation and, apparently, without changing DHA concentrations in serum or brain.     

Neuropeptide S reduces propofol- or ketamine-induced slow wave states through activation of cognate receptors in the rat

Intracerebroventricular injection of NPS reduces the duration of the ketamine- or thiopental-induced loss of the righting reflex in rats. But the specific EEG activities are unknown. We therefore sought to examine the effects of the NPS-NPSR system on anesthetic-induced characteristics of EEG power spectra and sleep-wake profiles. NPS alone or together with an NPSR antagonist was injected intracerebroventricularly, whereas the propofol (50 mg/kg) or ketamine (100 mg/kg) was administrated intraperitoneally. NPS (1 or 2 nmol) significantly reduced the amount of propofol-induced EEG delta activity and slow wave states (SWS). NPS (1 or 5 nmol) significantly reduced the amount of ketamine-induced SWS and EEG delta activity. Cortical EEG power spectral analysis showed that, in saline-pretreated rats, propofol induced a marked increase in delta (0.5–4 Hz) activity, decrease in theta (4.5–8.5 Hz) activity, and decrease in high frequency activity (14.5–60 Hz), while, in rats pretreated with 1 nmol of NPS, the duration of delta activity was reduced, while its spectral pattern was not changed. Whereas injection of ketamine into saline-pretreated rats induced a marked increase in delta (0.5–4 Hz) activity, a moderate increase in theta (4.5–8.5 Hz) activity, and a marked decrease in high frequency (14.5–60 Hz) activity. However, delta activity was reduced while theta activity increased under pretreatment with 1 nmol of NPS. The inhibitory effect of NPS on anesthetic-induced SWS was characterized by a reduced SWS episode duration with no significant change in either episode number or latency to SWS. [D-Val⁵]NPS, an NPSR antagonist (20 nmol), significantly attenuated the arousal-promoting effect of 1 nmol of NPS, but had no effect on SWS when injected alone. We speculate that NPS significantly reduces anesthetic-induced SWS and EEG slow activity by selective activation of the NPSR, which, in turn, would trigger subsequent arousal pathways.     

Effects of asenapine,olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat

BackgroundAsenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α₂-adrenergic than dopaminergic D₂ receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats.MethodsAfter operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or subchronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP.ResultsDeficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments.ConclusionThese data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.     

The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome

ObjectivesSleep disturbances are common in patients with fibromyalgia (FM). The objective of this analysis was to evaluate the effects of pregabalin on sleep in patients with FM.MethodsAnalyses were based on two randomized, double-blind, placebo-controlled trials of pregabalin (300 mg, 450 mg, and 600 mg daily) in adult FM patients. Sleep outcomes included the Medical Outcomes Study (MOS) Sleep Scale and a daily diary assessment of sleep quality. Treatment effects were evaluated using analysis of covariance. Clinically important differences (CID) in the Sleep Quality Diary and MOS Sleep Disturbance scores were estimated using mixed-effects models of changes in scores as a function of patients’ global impressions of change. Mediation modeling was used to quantify the direct treatment effects on sleep in contrast to indirect influence of the treatment on sleep via pain.ResultsA total of 748 and 745 patients were randomized in the respective studies. Patients were predominantly Caucasian females, average age 48–50 years, on average had FM for 9–10 years, and experienced moderate to severe baseline pain. Pregabalin significantly improved the Sleep Quality Diary (P < 0.001), MOS Sleep Disturbance (P < 0.01), MOS Quantity of Sleep (P < 0.003), and MOS Sleep Problems Index scores (P < 0.02) relative to placebo. Treatment effects for the 450 mg and 600 mg groups exceeded the estimated CID thresholds of 0.83 and 7.9 for the Sleep Quality Diary and MOS Sleep Disturbance scores, respectively. Mediation models indicated that 43–80% of the benefits on sleep (versus placebo) were direct effects of pregabalin, with the remainder resulting from an indirect effect of treatment via pain relief.ConclusionsThese data demonstrate improvement in FM-related sleep dysfunction with pregabalin therapy. The majority of this benefit was a direct effect of pregabalin on the patients’ insomnia, while the remainder occurred through the drug’s analgesic activity.     

Levetiracetam in submaximal subcutaneous pentylentetrazol-induced seizures in rats

Despite anticonvulsant efficacy in animal models of generalized epilepsy, levetiracetam was not effective in the maximal subcutaneous PTZ model in mice and rats.Aim of this study was to assess the efficacy of levetiracetam (LEV) against submaximal, s.c. MET test (PTZ at the dose of 70 mg/kg) acute seizures in Wistar rats, in comparison to valproic acid (VPA).Thirty male Wistar rats (P42) were divided in three drug-treatment groups (10 rats in each group) as follows: valproic acid, levetiracetam, and controls. All animals were tested for seizure threshold at age P50. VPA (110 mg/kg) and LEV (108 mg/kg) were freshly dissolved in saline and injected i.p. in 2–3 ml/kg, 15 and 30 min, respectively, before pentylenetetrazol (PTZ) injection at the dose of 70 mg/kg.The average latency of the seizure type 3 (generalized clonic seizure with loss of righting reflexes) significantly differed between controls and the drug-treated animal groups (p ≤ 0.02). The average duration of the seizure type 2 (threshold seizure) was significantly longer in both groups compared to controls (<0.02).In conclusion, LEV plays a role against seizures triggered by subcutaneous PTZ injection given at submaximal doses in rats, as demonstrated by a significant increase in duration of the seizure type 2 (threshold seizure).     

The effect of lamotrigine on learning in mice using the passive avoidance model

IntroductionLamotrigine (LTG) is an antiepileptic drug that inhibits the release of glutamate by blocking sodium channels. The present study was conducted to evaluate the effect of LTG in different stages of memory using a passive avoidance learning task in mice.MethodsMale albino mice in the weight range 20–25 g were used. They were divided into four groups (control group and three groups receiving various doses of LTG). LTG was given in three doses of 10, 25, and 50 mg/kg as intraperitoneal (IP) injections. The doses of LTG were used in three injection groups: before acquisition, after consolidation, and before retrieval at 24 h. The retention latency times in each group were recorded using a step-through passive avoidance task 24 h and one week after consolidation.ResultsRetention latency in the group receiving a high dose of LTG (25 mg/kg) after one week was significantly increased in comparison to the group receiving a low dose of LTG (10 mg/kg) (267 ± 49.96 vs. 198.87 ± 57.22, P = 0.015). With injection of LTG after consolidation, the retention latency times were increased in all doses after a one-week retrieval compared to the control (P = 0.023). Kaplan–Mayer surveillance analysis also showed significant differences in the latencies of the LTG-receiving group after 24 h and one week's retrieval (P = 0.041). Administration of LTG before retrieval at 24 h showed a significant difference in retention latency time, which was increased for two doses of LTG (10 and 50 mg/kg) after one week (203.5 ± 63.67 vs. 270.25 ± 19.78, P = 0.024).ConclusionLTG at higher doses may facilitate the learning process in mice and appears to improve memory function at different stages.     

Pregabalin increases slow-wave sleep and may improve attention in patients with partial epilepsy and insomnia

Insomnia is a common phenomenon particularly in patients with epilepsy. This study was performed to look at the effects of pregabalin, an anticonvulsant known to increase sleep depth and decrease arousals, in patients with insomnia and well-controlled epilepsy.MethodsThis was a double-blind, placebo-controlled, crossover study of subjects with insomnia and epilepsy. Each subject was treated with pregabalin 150 mg BID or placebo for two weeks, followed by a two-week washout period, then the other treatment for two weeks. Polysomnography and neuropsychological testing were performed at baseline and at the end of each treatment arm.ResultsThere was a significant increase in percentage of slow-wave sleep and a decrease in stage 1 sleep when subjects were taking pregabalin. Sleep efficiency increased during pregabalin treatment, although this was not statistically significant (84.5 +/? 4.6% for placebo versus 90.4 +/? 2.6% for pregabalin). There were a significant improvement in attention in the pregabalin group based on trial one of the Rey-Auditory Verbal Learning Test and a trend toward improvement in the psychomotor vigilance task; other neuropsychological measures were not significantly changed.ConclusionConcurrent treatment with pregabalin improves sleep depth in patients with insomnia and epilepsy and improves daytime attention.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52 h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1 mg/kg), clonidine (0.1 mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200 mg/kg), diazepam (1.5 and 2 mg/kg) or gabapentin (50 mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

Ectonucleotidase and acetylcholinesterase activities in synaptosomes from the cerebral cortex of streptozotocin-induced diabetic rats and treated with resveratrol

The aim of the present study was to investigate the effects of resveratrol (RV), an important neuroprotective compound on NTPDase, 5′-nucleotidase and acetylcholinesterase (AChE) activities in cerebral cortex synaptosomes of streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n = 8): control/saline; control/RV 10 mg/kg; control/RV 20 mg/kg; diabetic/saline; diabetic/RV 10 mg/kg; diabetic/RV 20 mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the cerebral cortex was removed for synaptosomes preparation and enzymatic assays. The results demonstrated that NTPDase and 5′-nucleotidase activities were significantly increased in the diabetic/saline group (p < 0.05) compared to control/saline group. Treatment with resveratrol significantly increased NTPDase, 5′-nucleotidase activities in the diabetic/RV10 and diabetic/RV20 groups (p < 0.05) compared to diabetic/saline group. When resveratrol was administered per se there was also an increase in the activities of these enzymes in the control/RV10 and control/RV20 groups (p < 0.05) compared to control/saline group. AChE activity was significantly increased in the diabetic/saline group (p < 0.05) compared to control/saline group. The treatment with resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups. In conclusion, this study demonstrated that the resveratrol interfere with the purinergic and cholinergic neurotransmission by altering NTPDase, 5′-nucleotidase and AChE activities in cerebral cortex synaptosomes of diabetic rats. In this context, we can suggest that resveratrol should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with the diabetes.     

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.     

The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats

ObjectiveRetigabine is a novel antiepileptic drug with a unique and complex mechanism of action which allows its use in many diseases associated with impaired neuronal activity. This study sought to examine the impact of retigabine on two types of memory in rats.MethodsAdult male Wistar rats were used to assess the effect of retigabine, administered p.o. as single (10 mg/kg or 20 mg/kg) or repeated doses, on spatial memory with the Morris water maze test (MWM) and emotional memory, associated with fear, with the passive avoidance test (PA).ResultsRetigabine administered at a high single dose transiently impairs learning processes in rats. In the MWM, these changes were delayed in time and of a lesser degree when retigabine was given at low single dose. Additionally, the drug administered repeatedly for 2 weeks slowed learning processes in the MWM, but this effect occurred only after 1 week of administration in the PA.ConclusionThese findings indicate that retigabine may affect memory and learning processes, especially in the first phase of administration.     

The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1 h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+ h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.     

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial

BackgroundAnimal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown.MethodsThis pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100 mg ketamine or 4.5 mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24 h–48 h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24 h–48 h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4 weeks prior to trial entry and throughout the trial.ResultsThe subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity.LimitationsPilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed.ConclusionsThese results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.     

Evaluation of the anticonvulsant effect of Centella asiatica (gotu kola) in pentylenetetrazol-induced seizures with respect to cholinergic neurotransmission

The study described here was carried out to investigate the anticonvulsant effect of different extracts of Centella asiatica with respect to cholinergic activity on pentylenetetrazol (PTZ)-induced seizures. Rats were randomly divided into eight groups of six rats each: nonepileptic rats treated with saline; PTZ (60 mg/kg, IP)-induced seizure rats treated with saline; PTZ-induced seizure rats pretreated with n-hexane, chloroform, ethyl acetate, n-butanol, and water extracts of C. asiatica; and PTZ-induced seizure rats pretreated with diazepam (2 mg/kg body wt). The seized rats pretreated with different extracts were administered a dose of 200 mg/kg body wt orally for 1 week before induction of epilepsy. Increased acetylcholine content and decreased acetylcholinesterase activity were recorded in different brain regions during PTZ-induced seizures. Pretreatment with C. asiatica extracts caused recovery of the levels of acetylcholine and acetylcholinesterase. These findings suggest that C. asiatica causes perceptible changes in the cholinergic system as one of the facets of its anticonvulsant activity.     

Effect of new neuronal growth factor on healing of sciatic nerve in rats

ObjectiveThe study aimed to investigate the effect of a new peptide new nerve growth factor (NNGF) on the healing of divided sciatic nerves in rats.Material and methodsTwenty Sprague–Dawley rats of 250–300 g were divided into two groups (group 1 — study group and group 2 — control group). Under ketamine intramuscular anesthesia sciatic nerves were exposed, divided and repaired using 10/0 dexon. Study animals had 10 mg/kg body weight of NNGF added to the repair. Electromyographic studies of the hind libs were carried out after 8 weeks. The average stimulation was 50 mA for 200 μS and four twitches (T) were recorded. The animals were euthanized and the sciatic nerves were removed for histological analysis.ResultsThere were no deaths in either of the groups. Electromyographic study showed that in the control group the average T1–T4 was 0.587 ± 0.17% and in the study group the average was 87.89 ± 5.02% (p value of 0.001). Histologically the control group showed regenerated axons sprouting from the proximal segment of cut nerve with empty endoneurial channels, while in the study group whole nerve trunks were seen within endoneurial channels.ConclusionThis study shows that the NNGF has a positive influence on the experimental healing of sciatic nerves in animals.