Effect of antiepileptic drug levetiracetam on cochlear function.

BACKGROUND: Levetiracetam (LEV, 5-100 mg/kg) has been shown to prevent audiogenic seizures in a dose-dependent manner. This chemical is known to bind to synaptic vesicle protein 2A and inhibit l-type calcium channels, affecting neurotransmitter release. We hypothesize that the drug prevents audiogenic seizures partially by affecting cochlear neural response. METHODS: To test this hypothesis, rats were given 1000, 500, 50, or 0 mg/kg (saline control) LEV-injection. Distortion product otoacoustic emissions (DPOAE), reflecting outer hair cell (OHC) function, and cochlear compound action potentials (CAP), reflecting cochlear neural output, were recorded and compared pre- and post-LEV. RESULTS: 1000 mg/kg LEV-injection did not significantly affect DPOAE. The high dose LEV-injection, however, significantly reduced CAP amplitude resulting threshold shift (TS), prolonged CAP latency, and enhanced CAP forward masking. CAP latency and forward masking were significantly affected at the 500 mg/kg dose, but CAP-TS remained unchanged after LEV-injection. Interestingly, CAP latency wassignificantly prolonged, at least at the low stimulation levels, although the amplitude of CAP remained constant after a clinical dose of LEV-injection (50 mg/kg). DISCUSSION: Since the clinical dose of LEV-injection does not reduce CAP amplitude, the reduction of cochlear neural output is unlikely to be the underlying mechanism of LEV in the treatment of audiogenic seizure. The delayed cochlear neural response may be partially related to the prevention of audiogenic seizure. However, neuropharmacological changes in the central nervous system must play a major role in the treatment of audiogenic seizure, as it does in the treatment of focal epilepsy.

CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis.

Memory decline occurs due to various factors, including stress, depression, and aging, and lowers the quality of life. Several nutritional supplements and probiotics have been used to enhance memory function, and efforts have been made to develop mixed supplements with maximized efficacy. In this study, we aimed to examine whether a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, CCL01, enhances memory function and induces neurogenesis via nerve growth factor (NGF) induction. Firstly, we orally administered CCL01 to normal mice and assessed their memory function 4 weeks after the first administration by performing a step-through passive avoidance test. We found that CCL01 at 100 mg kg-1 treatment enhanced the fear-based memory function. By analyzing the expression of Ki-67 and doublecortin, which are the markers of proliferating cells and immature neurons, respectively, we observed that CCL01 induced neuronal proliferation and differentiation in the hippocampus of the mice. Additionally, we found that the expression of synaptic markers increased in the hippocampus of CCL01-treated mice. We measured the NGF expression in the supernatant of C6 cells after CCL01 treatment and found that CCL01 increased NGF release. Furthermore, treatment of CCL01-conditioned glial media on N2a cells increased neuronal differentiation via the TrkA/ERK/CREB signaling pathway and neurotrophic factor expression. Moreover, when CCL01 was administered and scopolamine was injected, CCL01 ameliorated memory decline. These results suggest that CCL01 is an effective enhancer of memory function and can be applied to various age groups requiring memory improvement.

Evaluation of Phytochemical, Antioxidant, and Memory-Enhancing Activity of Garuga pinnata Roxb. Bark and Bryophyllum pinnatum (Lam) Oken. Leaves.

Garugapinnata Roxb. (Burseraceae) is a medium-sized tree widely available all over the tropical regions of Asia. Bryophyllum pinnatum (Lam) Oken. (Crassulaceae) is an indigenous and exotic plant grown in tropical regions. Both plants have been used for their anti-inflammatory, antioxidant, anticancer, wound healing, antidiabetic activities, etc. This investigation was designed to explore the result shown by methanolic extract of Garuga pinnata bark and Bryophyllum pinnatum leaves, on cognitive power and retention of the memory in experimental mice along with quantification of phenolic compounds and DPPH radicals neutralizing capacity. The memory-enhancing activity was determined by the elevated plus-maze method in Scopolamine-induced amnesic mice, using Piracetam as allopathic and Shankhpushpi as ayurvedic standard drugs. Two doses (200 and 400 mg/kg p.o.) of both extracts were administered to mice up to 8 consecutive days; transfer latency of individual group was recorded after 45 minutes and memory of the experienced things was examined after 1 day. DPPH assay method and the Folin-Ciocalteu method were employed to determine antioxidant potency and total phenol amount, respectively. 400 mg/kg of the methanolic B. pinnatum bark extract significantly improved memory and learning of mice with transfer latency (TL) of 32.75 s, which is comparable to that of standard Piracetam (21.78 s) and Shankhpushpi (27.83 s). Greater phenolic content was quantified in B. pinnatum bark extract (156.80 ± 0.33 µg GAE/mg dry extract) as well as the antioxidant potency (69.77% of free radical inhibition at the 100 µg/mL concentration). Our study proclaimed the scientific evidence for the memory-boosting effect of both plants.

Wuzang Wenyang Huayu decoction regulates differentially expressed transcripts in the rats' hippocampus after cerebral hypoperfusion.

The modified Wenyang Huayu decoction has been widely used to treat vascular dementia in China for thousands of years. We have previously proved that a modified version, Wuzang Wenyang Huayu decoction has the potential to be a more effective clinical treatment that can attenuate cerebral ischaemic injury. However, the global transcript profile and signalling conduction pathways regulated by this recipe remains unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Two groups of rats were intragastrically treated Wuzang Wenyang Huayu 2.5 g/kg vs or Piracetam 0.15 g/kg for 2 weeks. Learning and memory abilities were measured with Morris water maze. Neuronal plasticity was observed by HE staining. Differentially expressed transcripts of rat hippocampus were analysed by transcriptomics with Illumina HiSeq2500 platform. Results showed that Wuzang Wenyang Huayu decoction significantly alleviated learning, memory deficits, coordination dysfunction and prevented hippocampus cellular injury; Results further revealed the increased gene expression in KEGG metabolic pathways (MT-ND2. MT-ND3, MT-ND4, MT-ND4L, MT-ND5 and MT-ATP8) and genes involved in signal transduction, carcinogenesis, immune system, endocrine system, nervous system etc (Results further revealed differential expression of genes involved in various systems, including MT-ND2) Our discovery is likely to provide new insights to molecular mechanisms of Wuzang Wenyang Huayu regarding hippocampal transcripts in a murine vascular dementia model.

Nose to Brain Delivery of Galantamine Loaded Nanoparticles: In-vivo Pharmacodynamic and Biochemical Study in Mice.

BACKGROUND: Presence of blood brain barrier is one of the major hurdle in drug delivery to brain for the treatment of neurological diseases. Alternative and more effective drug delivery approaches have been investigated for the drug targeting to brain in therapeutic range. OBJECTIVE: The present investigation was carried out to improve the galantamine bioavailability in brain by intranasal drug delivery through thiolated chitosan nanoparticles and compared to nasal and oral delivery of its solution using pharmacodynamic activity as well as biochemical estimation. METHODS: Thiolated chitosan (modified) nanoparticles were fabricated using modified ionic gelation method and intranasal delivery is evaluated by reversal of scopolamine induced amnesia and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. Scopolamine (0.4 mg/kg, i.p.) was used to induce amnesia. Piracetam (400mg/kg, i.p.) was used as positive control. Mice were treated with galantamine solution (4mg/kg) by oral and nasal route and formulated galantamine nanoparticles (equivalent to 4mg/kg) by intranasal administration for 7 successive days and the results were compared statistically. RESULTS: Intranasal delivery of galantamine loaded thiolated chitosan nanoparticles was found significant (p<0.05) as compared to oral and nasal administration of its solution, by pharmacodynamic study and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. CONCLUSION: Significant recovery in amnesia induced mice model by intranasal administration of galantamine loaded thiolated chitosan nanoparticles established the relevance of nose to brain delivery over the conventional oral therapies for the treatment of Alzheimer's disease.

Piracetam attenuates binge eating disorder related symptoms in rats.

Binge eating disorder (BED) is a stress-related disorder characterized by acute episodes of excessive food intake. Piracetam, a nootropic agent has been reported to show several other neuropharmacological properties. The present study, evaluated the pharmacological effect of piracetam (200 mg/kg i.p.) on BED in female rats, induced by free access to palatable cookies for 2 h on alternate days. BED was confirmed by an increase in binge eating behavior and weight gain. BED leads to anxiety, cognitive and memory deficits, as evaluated by EPM (Elevated plus maze), OFT (open field test), and Y-maze tests. Increased levels of plasma corticosterone (CORT), glutamate in nucleus accumbens (NAC), hypothalamus (HYP) and prefrontal cortex (PFC) indicate stress and excitotoxicity. Moreover, it was observed that the levels of dopamine were higher in NAC and PFC, and less in HYP which may be responsible for motivational behavior for palatable feeding and cognitive deficits. More surprisingly, feeding behaviour regulating hormones namelyleptin was increased and ghrelin level was decreased in BED. Further, level of acetylcholine which regulates cognitive behaviour was compromised in BED. Piracetam significantly decreased binge eating behavior and associated body weight and regulated the levels of concerned neurotransmitters in respective regions. However, piracetam did not alter normal feeding behavior in the fast-refed model. Further, piracetam showed brain region-specific decrease in vascular endothelial growth factor expression. Piracetam showed anxiolytic activity and also alleviated cognitive deficit observed in BED. Hence, preclinical evidence indicates the potential use of piracetam for the treatment of BED.

Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2.

ETHNOPHARMACOLOGICAL RELEVANCE: Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. AIM OF THE STUDY: The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. MATERIALS AND METHODS: PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. RESULTS: Chronic treatment of large dose of D-gal/NaNO2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on brain AChE activity. CONCLUSION: PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO2-induced senile mice, similar to piracetam. This phenolic extract provides a promising candidate for prevention of aging and aging-related cognitive dysfunction in clinic.

Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients.

Secondary paroxysmal dyskinesias (SPDs) are short, episodic, and recurrent movement disorders, classically related to multiple sclerosis (MS). Carbamazepine is effective, but with risk of adverse reactions. We identified 7 patients with SPD among 457 MS patients (1.53%). SPD occurred in face ( n = 1), leg ( n = 2), or arm +leg ( n = 4) several times during the day. Magnetic resonance imaging (MRI) showed new or enhancing lesions in thalamus ( n = 1), mesencephalic tegmentum ( n = 1), and cerebellar peduncles ( n = 5). Patients were treated with clonazepam and then acetazolamide ( n = 1), acetazolamide ( n = 5), or levetiracetam ( n = 1) with response within hours (acetazolamide) to days (levetiracetam). No recurrences or adverse events were reported after a median follow-up of 33 months.

Piracetam Facilitates the Anti-Amnesic but not Anti-Diabetic Activity of Metformin in Experimentally Induced Type-2 Diabetic Encephalopathic Rats.

Piracetam exhibits anti-amnesic activity in several animal models of dementia. However, its anti-amnesic potential has yet to be evaluated in type-2 diabetes mellitus (T2DM)-induced encephalopathy. Therefore, in the present study, piracetam (25, 50 and 100 mg/kg) was screened for anti-amnesic and anti-diabetic activity in T2DM-induced encephalopathic male rats. Subsequently, anti-amnesic and anti-diabetic activities were evaluated for piracetam, metformin and their combination in T2DM-induced encephalopathic animals. Rats received streptozotocin (45 mg/kg) and nicotinamide (110 mg/kg) injections on day-1 (D-1) of the experimental schedule and were kept undisturbed for 35 days to exhibit T2DM-induced encephalopathy. All drug treatments were continued from D-7 to D-35 in both experiments. Piracetam (100 mg/kg) attenuated loss in learning and memory in terms of increase in escape latency on D-4 (D-34) and decrease in time spent in the target quadrant on D-5 (D-35) of Morris water maze test protocol, and spatial memory in terms of reduced spontaneous alternation behavior in Y-maze test of encephalopathic rats. Additionally, piracetam attenuated altered levels of fasting plasma glucose and insulin, HOMA-IR and HOMA-B in encephalopathic animals, comparatively lesser than metformin. In the next experiment, combination of piracetam and metformin exhibited better anti-amnesic but not anti-diabetic activity than respective monotherapies in encephalopathic rats. Further, the combination attenuated reduced acetylcholine level and increased acetylcholinesterase activity, increased glycogen synthase kinase-3ß level and decreased brain-derived neurotropic factor level in hippocampus and pre-frontal cortex of encephalopathic animals. Thus, piracetam could be used as an adjuvant to metformin in the management of dementia in T2DM-induced encephalopathy.

Resting-state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign epilepsy with central-temporal spikes.

OBJECTIVES: Our aim was to investigate regional difference in brain activities in response to antiepileptic drug (AED) medications in benign epilepsy with central-temporal spikes (BECTS) using resting-state functional magnetic resonance imaging (fMRI). METHODS: Fifty-seven patients with BECTS underwent resting-state fMRI scans after receiving either valproic acid (VPA) (n = 15), levetiracetam (LEV) (n = 21), or no medication (n = 21). fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared and were correlated with total doses of AED in the two medicated groups. RESULTS: Compared with patients on no-medication, patients receiving either VPA or LEV showed decreased ReHo in the central-temporal region, frontal cortex, and thalamus. In particular, the VPA group showed greater ReHo decrease in the thalamus and milder in cortices and caudate heads compared with the LEV group. In addition, the VPA group demonstrated a negative correlation between ReHo values in the central-temporal region and medication dose. CONCLUSION: Both VPA and LEV inhibit resting-state neural activity in the central-temporal region, which is the main epileptogenic focus of BECTS. VPA reduced brain activity in the cortical epileptogenic regions and thalamus evenly, whereas LEV reduced brain activity predominantly in the cortices. Interestingly, VPA showed a cumulative effect on inhibiting brain activity in the epileptogenic regions in BECTS. KEY POINTS: • Regional differences in brain activity in response to different AEDs in BECTS. • AEDs inhibit resting-state neural activity in epileptogenic and subcortical regions in BECTS. • Valproic acid effect on the cortical epileptogenic regions and thalamus evenly. • Levetiracetam effect seen predominantly in cortices. • Valproic acid has a cumulative effect on inhibiting brain activity in epileptogenic regions.

Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells.

It was shown for the first time that the endogenous cyclic dipeptide cycloprolylglycine (CPG) at concentrations of 10(-7) and 10(-3) M and piracetam at a concentration of 10(-3) M increased the content of brainderived neurotrophic factor (BDNF) in the culture of neuronal cells in normal state and under conditions of glutamate and 6-oxydopamine neurotoxicity. This may indicate the possible involvement of BDNF in the mechanism of action of neuropeptide CPG and piracetam.

Racemic oleracein E increases the survival rate and attenuates memory impairment in D-galactose/NaNO2-induced senescent mice.

BACKGROUND: Compounds that possess a pyrrolidone skeleton are a rich resource for the discovery of nootropic drugs. Oleracein E (OE), which possesses both tetrahydroisoquinoline and pyrrolidone skeletons, was first isolated from the medicinal plant Portulaca oleracea L. and was thought to be an active component in the cognition-improvement effect induced by this herb. The aim of this study was to investigate the effect of OE on cognitive impairment in senescent mice and its underlying mechanism of action. METHOD: Senescent Kunming mice were established by the intraperitoneal injection of D-galactose (D-gal, 1250 mg/kg/d) and NaNO2 (90 mg/kg/d) for 8 weeks. OE (3 mg/kg/d, 15 mg/kg/d) was orally administered for 8 weeks, and the nootropic drug piracetam (PA, 400 mg/kg/d) was used as a positive control. A Morris water maze was used to assess cognitive ability. GSH and MDA levels and T-AOC, SOD, and CAT activities in the brain or plasma were determined. Hippocampal morphology was observed by HE staining, and expression of the anti-apoptotic protein Bcl-2 and the pro-apoptotic proteins Bax and Caspase-3 was observed by immunohistochemical staining. RESULTS: Large-dosage treatments with D-gal/NaNO2 for 8 weeks significantly reduced survival, impaired spatial memory capacity, compensatorily up-regulated GSH level and T-AOC and SOD activities, decreased CAT activity, and induced hippocampal neuronal damage and apoptosis as reflected by the apparent low expression of Bcl-2 and high expression of Bax and Caspase-3. OE significantly prolonged lifespan and was more potent than PA. Similar to PA, OE at 15 mg/kg/d improved memory capacity. The underlying mechanism of action was related to the reversal of abnormal brain antioxidant biomarkers (GSH, T-AOC, and SOD) to normal levels and the inhibition of hippocampal neuronal apoptosis. CONCLUSION: OE from P. oleracea is an active compound for improving cognitive function and is also a candidate nootropic drug for the treatment of age-related dementia.

Levetiracetam prophylaxis ameliorates seizure epileptogenesis after fluid percussion injury.

To determine whether post-traumatic seizure severity would be affected by the interval between seizures and head injury, we measured seizures after various times with or without fluid percussion brain injury (2atm fluid percussion injury; FPI). To determine efficacy of anti-seizure medication, we also determined if levetiracetam (LEV) would alter the relationship between injury and subsequent seizures. Early post-traumatic seizures were induced by Kainic acid (KA) at one week after 2atm fluid percussion injury (FPI) in one group (FPI-ES). Seizures were induced at two weeks after FPI by KA in another group (FPI-LS). In addition, one group had induced seizures by KA without FPI, (sham-ES). Finally one group of animals received the antiepileptic agent (levetiracetam) infusion for one week after FPI and then had seizures induced by KA (FPI-LEV-ES). We measured seizure onset time, ictal duration and severity of seizures using a modified Racine's scale. Histopathological changes in the hippocampus CA1 region were also analyzed. Severity of seizures were increased in the FPI-ES group compared with sham-ES animals. Severity was also enhanced in early post-injury seizures induced by KA (FPI-ES vs. FPI-LS); this exacerbation of seizure severity could be ameliorated by levetiracetam infusion (FPI-ES vs. FPI-LEV-ES). Neuronal degeneration in CA1 was more severe in the FPI-ES group and this degeneration was also diminished by LEV. We conclude that early post injury seizures exacerbate susceptibility and severity of post traumatic seizures and increase neuronal degeneration in the CA1 layer of hippocampus. These changes are partially reversed by LEV infusion after FPI.

Piracetam prevents memory deficit induced by postnatal propofol exposure in mice.

Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis.

Omega 3 polyunsaturated fatty acids enhance the protective effect of levetiracetam against seizures, cognitive impairment and hippocampal oxidative DNA damage in young kindled rats.

Levetiracetam (LEV) is a unique, effective, relatively safe antiepileptic drug that preferentially interacts with synaptic vesicle protein 2A (SV2A). This study aimed to explore the effect of combined treatment of LEV with omega 3 (OM3) on cognitive impairment and hippocampal oxidative stress and DNA damage induced by seizures in the PTZ-kindled young rat model. Cognitive functions, biomarkers of oxidative stress, and DNA damage were assessed in PTZ-kindled young rats pretreated with single and combined treatment of LEV (30mg/kg, i.p.) and OM3 (200mg/kg, p.o.). Pretreatment with LEV and OM3 at the tested doses significantly attenuated PTZ-induced seizures and decreased cognitive impairment in both passive avoidance and elevated plus maze tests in the PTZ-kindled rats. Moreover, the increase in hippocampal glutamate, malondialdehyde and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, as well as the decrease in reduced glutathione (GSH) levels and GSH-peroxidase and superoxide dismutase activities induced by PTZ kindling, significantly decreased. These effects were higher with combined treatment of LEV with OM3 and significantly more than the observed effects of single LEV or OM3. In conclusion, the combined treatment of LEV with OM3 is more effective in seizure control and alleviating the cognitive impairment induced by PTZ kindling in the young rat model, the effects that result from the decrease in hippocampal oxidative stress and DNA damage which can be attributed to the antioxidant properties of both LEV and OM3. These results may be promising for the use of LEV and OM3 combination in the treatment of epileptic children.

Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy.

Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.

Nootropic effect of meadowsweet (Filipendula vulgaris) extracts.

The effects of the extracts of the aboveground parts of Filipendula vulgaris Moench on the behavior and memory of mice after hypoxic injury and their physical performance in the open-field test were studied using the models of hypoxia in a sealed volume, conditioned passive avoidance response (CPAR), and forced swimming with a load. The extracts improved animal resistance to hypoxia, normalized orientation and exploration activities, promoted CPAR retention after hypoxic injury, and increased physical performance. Aqueous extract of meadowsweet had the most pronounced effect that corresponded to the effect of the reference drug piracetam. These effects were probably caused by modulation of hippocampal activity.

Effect of quercetin and rutin in some acute seizure models in mice.

Quercetin is one of the most widely occurring flavonoid which is also often present in plants as glycosidic form - rutin. These compounds are ingredients of plant diet and are also present in numerous pharmaceutical preparations and diet supplements which are taken by patients suffering from epilepsy and treating with antiepileptic drugs (AEDs). Influence of these compounds on central nervous system-related effects was proved both in experimental and clinical studies. Their influence on anxiety, depression, memory processes and convulsant activity was reported. The aim of the present study was to investigate the effect of quercetin and rutin in some models of seizures, i.e., in the model of psychomotor seizures induced by 6Hz stimulation, in the maximal electroshock seizure threshold and intravenous pentylenetetrazole tests in mice. We also examined a possible mechanism of anticonvulsant activity of quercetin and its influence on action of two AEDs, i.e., valproic acid and levetiracetam, in the 6Hz seizure test. Our results revealed only a weak anticonvulsant potential of the studied flavonoids because they showed anticonvulsant action at doses from 10 to 200mg/kg only in the 6Hz test and did not change seizure thresholds in the remaining tests. Moreover, anticonvulsant action of the studied flavonoids was short-term, noted only at pretreatment time ranging between 30 and 60min. The highest anticonvulsant activity of quercetin was correlated with its high plasma and brain concentration, which was revealed in a pharmacokinetic study. We did not note changes in the anticonvulsant action of the used AEDs combined with quercetin in the model of psychomotor seizures in mice. Neither quercetin and rutin nor combinations of quercetin with the studied AEDs produced any significant impairments of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test) and long-term memory (evaluated in the passive avoidance test) in mice. The results of the present study suggest that quercetin and rutin have only weak and short-term anticonvulsant potential. These flavonoids seem to be safe for patients with epilepsy because they neither changed activity of the studied AEDs nor produced any adverse effects.

[Cognitive abilities of rats in behavior of the active avoidance in age differences].

The components of cognitive operant behavior of rats was investigated after preliminary development of a unilateral conditioned reinforcement reflex of an active avoidance aversive stimulus in the problem chamber. It is established, that cognitive abilities associated with phenotypes factors, as age and a sex. In applied aspect of research comparable actions by efficiency with Pyracetamum are reveal nootrop and activating properties at the Chinese vegetative preparation. Use of neurotropic preparations has allowed reveal their positive and negative influence on primary mental components operant behavior of an active avoidance.

Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats.

Current treatment of nerve agent poisoning with ionotropic drugs proves inadequate, and alternative treatment strategies are searched for. Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20 min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20 min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. Metabotropic glutamate receptor modulators may represent an alternative or supplement to treatment with ionotropic drugs.