Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase

BACKGROUND AND PURPOSES

Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2.

EXPERIMENTAL APPROACH

Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia).

KEY RESULTS

In male rats with tMCAO, HYDAMTIQ (0.1–10 mg·kg⁻¹) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO.

CONCLUSION AND IMPLICATIONS

Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.     

The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice

BACKGROUND AND PURPOSE

20-Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20-Hydroxyeicosatetraenoic acid synthesis, TS-011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS-011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS-011 on microvessels after cerebral ischaemia.

EXPERIMENTAL APPROACH

TS-011 (0.3 mg·kg⁻¹) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels were measured using in vivo two-photon imaging.

KEY RESULTS

The cerebral blood flow velocities in the peri-infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle-treated mice. We found that TS-011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri-infarct microvessels seen in the vehicle-treated mice after reperfusion. In addition, TS-011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle-treated group. Moreover, TS-011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion.

CONCLUSIONS AND IMPLICATIONS

These findings demonstrated that infusion of TS-011 improved defects in the autoregulation of peri-infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia.     

RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats

Aim:

To test the role of the Beclin 1-dependent autophagy pathway in brain damage during cerebral ischemia.

Methods:

Focal cerebral ischemia was established in rats using a middle cerebral artery occlusion (MCAO) model. A lentiviral vector-associated RNA interference (RNAi) system was stereotaxically injected into the ipsilateral lateral ventricle to reduce Beclin1 expression. We measured the ipsilateral infarct volume, autophagosome formation, neurogenesis and apoptosis, all of which could be modulated by Beclin1 RNAi.

Results:

On the 14th day after MCAO, Beclin1 downregulation by RNAi increased the population of neural progenitor cells (BrdU⁺-DCX⁺), newborn immature cells (BrdU⁺-Tuj-1⁺) and mature neurons (BrdU⁺-MAP-2⁺), and reduced the apoptosis of immature neurons (caspase-3⁺-DCX⁺ and caspase-3⁺-Tuj-1⁺) surrounding the ischemic core of the ipsilateral hemisphere. Furthermore, RNAi-mediated downregulation of Beclin1 decreased infarct volume and inhibited histological injury and neurological deficits.

Conclusion:

RNAi-mediated downregulation of Beclin1 improves outcomes after transient MCAO.     

Inhibition of central angiotensin-converting enzyme with enalapril protects the brain from ischemia/reperfusion injury in normotensive rat

Background and the Purpose of the study

Central Angiotensin Converting Enzyme (ACE) has an important role on cerebral microcirculation and metabolism. However, its role in terms of protecting the brain from ischemic/reperfusion (I/R) injury are debatable. This study evaluated the role of ACE, using enalapril as ACE inhibitor, in protection of the brain from I/R injury during transient focal cerebral ischemia (TFCI) in normotensive rat.

Method

Male Sprague Dawley rats (280–320g) randomly assigned to control ischemic and enalapril pre-treated ischemic groups. Enalapril was injected intraperitoneally 1 h before middle cerebral artery occlusion (MCAO) at the dose of 0.03 or 0.1 mg/kg. Cerebral ischemia was induced by 60 min MCAO followed by 24 hrs reperfusion. After evaluation of neurological deficit scores (NDS) the animal was sacrificed for assessment of cerebral infarction and edema.

Results

TFCI induced cerebral infarctions (283±18 mm³), brain edema (4.1±0.4%) and swelling (9.8±1.5%) with NDS of 3.11±0.36. Non-hypotensive dose of enalapril (0.03 mg/kg) improved NDS (1.37±0.26), reduced cerebral infarction (45%), brain edema (54%) and swelling of the lesioned hemispheres (34%) significantly. However, hypotensive dose of enalapril (0.1 mg/kg) could improve neurological activity (1.67±0.31) and failed to reduce cerebral infarction (276±39 mm³) and swelling (10.4±1.4%).

Conclusion

In the rat model of transient focal cerebral ischemia, inhibition of angiotensin converting enzyme with non-hypotensive doses of enalapril has the benefit of improving neurological activity, reducing cerebral infarction, brain swelling and edema of acute ischemic stroke. Therefore, it is reasonable to conclude that central renin-angiotensin system may participate in ischemic/reperfusion injury of the cerebral cortex.     

Effects of Semelil (ANGIPARS™) on focal cerebral ischemia in male rats

Background and the purpose of the study

Cerebral ischemia is one of the main causes of long term disability and death in aged populations. Many herbal drugs and extracts have been used for the treatment of cerebral ischemia induced insults. This study was designed to investigate the protective effect of Semelil (ANGIPARS™), a new herbal drug, on focal cerebral ischemia in male rats.

Material and methods

Male rats were divided into five groups: sham-operated, ischemic animals treated with distilled water as vehicle, ischemic animals treated with 1, 10 and 100 mg/kg of Semilil respectively. Middle cerebral artery occlusion (MCAO) model was used in NMRI rats and neuronal injury analyzed in hippocampal CA1 sector after 48 hrs of Middle Cerebral Artery (MCAO).

Results

Results of this study showed that treatment with semelil attenuated ischemic damages and has positive effects on focal cerebral ischemia.     

Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia

Aim:

To examine the effects of a mixed formulation composed of prostaglandin E1 and lithium (PGE1+Li mixture) on brain damage after cerebral ischemia. The effects of the mixture on protein expression of heat shock proteins (HSPs), p53, and Bcl-2 were also determined.

Methods:

Brain ischemia was induced with a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were treated with a single intravenous administration of PGE1, lithium or a PGE1+Li mixture immediately after the ischemic insult. The infarct volume and motor behavior deficits were analyzed 24 h after the ischemic insult. The protein levels of HSP70, glucose-regulated protein 78 (GRP78), HSP60, Bcl-2, and p53 in the striatum of the ipsilateral hemisphere were examined using immunoblotting.

Results:

The mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg) reduced infarct volume and neurological deficits induced by focal cerebral ischemia. Moreover, the mixture had a greater neuroprotective effect against cerebral ischemia compared with PGE1 or lithium alone. The mixture was effective even if it was administered 3 h after ischemia. PGE1+Li also significantly upregulated cytoprotective HSP70, GRP78, HSP60, and Bcl-2 protein levels, while decreasing p53 expression.

Conclusion:

These results demonstrated a PGE1+Li mixture with a therapeutic window of up to 3 h for clinical treatment of cerebral ischemia. The PGE1+Li mixture potentially exerts a protective effect after stroke through the induction of HSPs and Bcl-2 proteins.     

Cardioprotective effect of fenugreek on isoproterenol-induced myocardial infarction in rats

Objectives:

This study is designed to evaluate the cardioprotective effect of fenugreek on isoproterenol- induced myocardial infarction and is investigated by an in vivo method in rats.

Materials and Methods:

Male Wistar albino rats were divided into four groups (n=10). Group I received 0.5% CMC treated as normal control group. Group II received isoproterenol (85 mg/kg body weight) intraperitoneal (i.p.) for two consecutive days (14^th and 15^th days). Group III received fenugreek (250 mg/kg body weight) intragastric intubation for 15 days. Group IV rats received fenugreek as in Group III and additionally isoproterenol was given for two consecutive days (14^th and 15^th days).

Results:

The results described the cardioprotective effect that observed in Group IV showed significantly (P< 0.05) decreased levels of TBARS and enhanced the activities of both enzymatic and non-enzymatic antioxidants (SOD, CAT, GPx and GSH) in myocardial infarcted rats when compared to Groups II and III. Histopathological studies were also co-relating with the above biochemical parameters.

Conclusion:

These findings concluded the cardioprotective effect of fenugreek on lipid peroxidation and antioxidant defense system during isoproterenol-induced myocardial infarction in rats.     

Evaluation of antidepressant activity of tramadol in mice

Objective:

To evaluate antidepressant like effect of tramadol in mice.

Materials and Methods:

Tramadol was administered at three different doses (10,20 and 40 mg/kg, i.p) once daily for 7 days to Swiss albino mice of either sex. The immobility period of control and drug treated mice were recorded in tail suspension test (TST).The antidepressant effect of tramadol was compared to that of fluoxetine (20 mg/kg, i.p), administered for seven days.

Results:

Tramadol produced significant antidepressant effect at all the doses, as indicated by reduction in immobility times as compared to control. The efficacy of tramadol at doses of 20 and 40 mg/kg was comparable with that of fluoxetine. Tramadol at 10 mg/kg dose showed significantly less antidepressant activity compared to fluoxetine.

Conclusion:

The results of the present study indicate antidepressant like activity of tramadol.     

In vivo effects of Ginkgo biloba extract on interleukin-6 cytokine levels in patients with neurological disorders

Objective:

To evaluate the effect of Ginkgo biloba extract (EGB) on the serum levels of cytokines in patients suffering from chronic, age-related neurological disorders (NDs).

Materials and Methods:

Patients received 9.6 mg of EGB twice daily for 8 weeks. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA) before and after treatment.

Results:

The serum level of IL-6 was significantly higher in ND patients as compared to the healthy controls. After these patients underwent 4 and 8 weeks of EGB treatment, their IL-6 levels were shown a statistically significant (P<0.05) decline to near normal values. No significant changes were observed in serum levels of IL-1β and TNF-α after EGB treatment. We also observed an inverse relationship between ND and serum cholesterol levels.

Conclusions:

EGB may exert its beneficial effects in patients suffering from NDs through down-regulation and suppression of IL-6 secretion.KEY WORDS: ELISA, interleukin-6, Ginkgo biloba extract, neurological disorder     

Hepatoprotective activity of aqueous extract of Portulaca oleracea in combination with lycopene in rats

Objective:

To investigate the hepatoprotective activity of the aqueous extract of the aerial parts of Portulaca oleracea (P. oleracea) in combination with lycopene against carbon tetrachloride induced hepatotoxicity in rats.

Materials and Methods:

Hepatotoxicity was induced in male Wistar rats by intraperitoneal injection of carbon tetrachloride (0.1 ml/kg b.w for 14 days). The aqueous extract of P. oleracea in combination with lycopene (50 mg/kg b.w) was administered to the experimental animals at two selected doses for 14 days. The hepatoprotective activity of the combination was evaluated by the liver function marker enzymes in the serum [aspartate transaminases (AST), alanine transaminases (ALT), alkaline phosphatase (Alk.P), total bilirubin (TB), total protein (TP) and total cholesterol (TC)], pentobarbitone induced sleeping time (PST) and histopathological studies of liver.

Results:

Both the treatment groups showed hepatoprotective effect against carbon tetrachloride induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal which was comparable to that of silymarin group. Besides, the results obtained from PST and histopathological results also support the study.

Conclusions:

The oral administration of P. oleracea in combination with lycopene significantly ameliorates CCl₄ hepatotoxicity in rats.     

Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: Prediction of quick onset of antidepressant action

Objectives:

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant drugs. The addition of low dose of 5-hydroxytryptamine type 2A enhances the therapeutic effect of SSRIs. The purpose of the present studies was to test the effects of combined treatment of a low dose of ketanserin (KET) and escitalopram (ESC) on behavioral anomalies occurring after olfactory bulbectomy (OBX).

Materials and Methods:

Chronic Depression was induced by OBX as shown in behavioral tests such as Open field, social interaction, and hyperemotionality tests. Acute and chronic treatment effect of KET, ESC, and combination was administered to the OBX rats.

Results:

Chronic (14 days) treatment with KET (1 mg/kg) or ESC (10 mg/kg) alleviated the behavioral anomalies of olfactory bulbectomized rats in modified open field exploration, social interaction, hyperemotionality. When KET treatment was combined with ESC, a short duration regimen (7 days) was sufficient to reverse the bulbectomy-induced anomalies.

Conclusion:

The combination therapy as a likely strategy to achieve an early-onset of antidepressant action.KEY WORDS: Antidepressant action, escitalopram, ketanserin, olfactory bulbectomy     

Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice

Background and purpose:

Reactive oxygen species (ROS) derived from Nox2-containing reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is reportedly detrimental in cerebrovascular disease. However, ROS generation by other Nox isoforms may have a physiological role. No Nox2-selective inhibitors have yet been identified, and thus it is unclear whether isoform non-selective Nox inhibitors would necessarily improve outcome after stroke. We assessed the effect of apocynin on cerebrovascular ROS production and also on outcome following cerebral ischaemia when administered either before ischaemia or after cerebral reperfusion. The involvement of Nox2-containing NADPH oxidase in the effects of apocynin was assessed using Nox2^−/− mice.

Experimental approach:

Transient cerebral ischaemia was induced by 0.5 h middle cerebral artery occlusion followed by 23.5 h reperfusion. Mice received apocynin (2.5 mg·kg⁻¹, i.p.) either 0.5 h before ischaemia or 1 h after reperfusion. In situ superoxide production after cerebral ischaemia-reperfusion was measured in brain sections of wild-type mice at 24 h using dihydroethidium fluorescence.

Key results:

Treatment with apocynin 0.5 h before ischaemia reduced total infarct volume, neurological impairment and mortality in wild-type but not Nox2^−/− mice. Conversely, treatment with apocynin 1 h after initiation of reperfusion had no protective effect. Cerebral ischaemia and reperfusion increased superoxide production in the brain at 24 h, and pretreatment but not posttreatment with apocynin reduced superoxide levels.

Conclusions and implications:

Apocynin improves outcome following stroke when administered before ischaemia in wild-type but not Nox2^−/− mice.     

Drug safety monitoring in patients of movement disorders of a tertiary care hospital

Background:

Movement disorders (MD) are neurological conditions that affect the speed, fluency, quality, and ease of movement and commonly include Parkinson’s disease, tremor and dystonias. Drugs are important causes of MD, and the incidence and prevalence of such disorders are possibly underappreciated because of the lack of recognition.

Objectives:

To assess the incidence of all adverse drug reactions (ADRs) and estimate the prevalence of drug-induced MD among patients attending the clinic.

Materials and Methods:

This prospective observational study was conducted at an outpatient referral MD clinic of a tertiary care hospital for 1 year. The demographic data, drug intake, diagnosis, and ADRs experienced by the subjects were recorded. Causality assessment was done by Naranjo’s scale.

Results:

Incidence of ADR among patients who attended this clinic was 19.7% (151 out of 768 patients experienced at least one ADR). A total of 299 ADRs were detected out of which 30.8% were gastrointestinal, 28.4% psychiatric, and 26% MD effects. The commonly implicated suspect drugs were levodopa (37.8%) and trihexyphenidyl (25.1%). The prevalence of drug-induced MD was 10.15% and drug-induced dyskinesias and dystonias were the most common.

Conclusion:

MDs are clinically important neurological disorders which are often caused by drugs and interestingly drugs used for its management are also associated with high incidence of ADRs. Hence these ADRs should be carefully monitored.     

WIN55,212-2 protects oligodendrocyte precursor cells in stroke penumbra following permanent focal cerebral ischemia in rats

Aim:

To explore whether the synthetic cannabinoid receptor agonist WIN55,212-2 could protect oligodendrocyte precursor cells (OPCs) in stroke penumbra, thereby providing neuroprotection following permanent focal cerebral ischemia in rats.

Methods:

Adult male SD rats were subjected to permanent middle cerebral artery occlusion (p-MCAO). The animals were administered WIN55,212-2 at 2 h, and sacrificed at 24 h after the ischemic insult. The infarct volumes and brain swelling were assessed. The expression of cannabinoid receptor type 1 (CB1) in the stroke penumbra was examined using Western blot assay. The pathological changes and proliferation of neural glial antigen 2-positive OPCs (NG2⁺ cells) in the stroke penumbra were studied using immunohistochemistry staining.

Results:

p-MCAO significantly increased the expression of CB1 within the stroke penumbra with the highest level appearing at 2 h following the ischemic insult. Administration of WIN55,212-2 (9 mg/kg, iv) significantly attenuated the brain swelling, and reduced the infarct volume as well as the number of tau-immunoreactive NG2⁺ cells (tau-1⁺/NG2⁺ cells) in the stroke penumbra. Moreover, WIN55,212-2 significantly promoted the proliferation of NG2⁺ cells in the stroke penumbra and in the ipsilateral subventricular zone at 24 h following the ischemic insult. Administration of the selective CB1 antagonist rimonabant (1 mg/kg, iv) partially blocked the effects caused by WIN55,212-2.

Conclusion:

Tau-1 is expressed in NG2⁺ cells following permanent focal cerebral ischemic injury. Treatment with WIN55,212-2 reduces the number of tau-1⁺/NG2⁺ cells and promotes NG2⁺ cell proliferation in the stroke penumbra, which are mediated partially via CB1 and may contribute to its neuroprotective effects.     

Pharmacodynamic interaction study of Allium sativum (garlic) with cilostazol in patients with type II diabetes mellitus

Aim:

Garlic is available as an over-the-counter herbal supplement and is known to have antiplatelet properties. Because of scarcity of clinical data regarding the safety of concomitant use of garlic supplements and anticoagulants, we tried to evaluate the effects of coadministration of single and multiple doses of garlic and cilostazol on platelet aggregation.

Materials and Methods:

The study was a randomized, open label, placebo-controlled, crossover study of type II diabetic patients, where 14 patients were enrolled and 10 completed the study. The patients were administered 600 mg aged garlic extract, 100 mg cilostazol, 600 mg aged garlic extract, and cilostazol or placebo for seven days as per prior randomization schedule. Blood samples for platelet aggregation and bleeding time and clotting time were collected before and 2, 4, and 6 hours after single-dose drug administration and after seven days of treatment.

Results:

After single- and multiple-dose administration of garlic, there was a significant inhibition of platelet aggregation at 2 hours, whereas with cilostazol, the inhibition was significant at all the three time points tested, with 4 hours showing maximum inhibition. Coadministration of garlic and cilostazol in single and multiple doses for seven days did not produce any significant change in the antiplatelet activity of the individual drugs.

Conclusions:

Coadministration of aged garlic extract and cilostazol did not enhance the antiplatelet activity compared with individual drugs. Large randomized trials are needed to further evaluate the possible interaction of garlic in higher doses and in combination with other antiplatelet activity drugs.     

Efficacy study of Prunus amygdalus (almond) nuts in scopolamine-induced amnesia in rats

Objective:

Cognitive disorders such as amnesia, attention deficit and Alzheimer’s disease are emerging nightmares in the field of medicine because no exact cure exists for them, as existing nootropic agents (piractam, tacrine, metrifonate) have several limitations. The present study was undertaken to investigate the effect of Prunus amygdalus (PA) nuts on cognitive functions, total cholesterol levels and cholinesterase (ChE) activity in scopolamine-induced amnesia in rats.

Materials and Methods:

The paste of PA nuts was administered orally at three doses (150, 300 and 600 mg/kg) for 7 and 14 consecutive days to the respective groups of rats. Piracetam (200 mg/kg) was used as a standard nootropic agent. Learning and memory parameters were evaluated using elevated plus maze (EPM), passive avoidance and motor activity paradigms. Brain ChE activity and serum biochemical parameters like total cholesterol, total triglycerides and glucose were evaluated.

Results:

It was observed that PA at the above-mentioned doses after 7 and 14 days of administration in the respective groups significantly reversed scopolamine (1 mg/kg i.p.)-induced amnesia, as evidenced by a decrease in the transfer latency in the EPM task and step-down latency in the passive avoidance task. PA reduced the brain ChE activity in rats. PA also exhibited a remarkable cholesterol and triglyceride lowering property and slight increase in glucose levels in the present study.

Conclusion:

Because diminished cholinergic transmission and increase in cholesterol levels appear to be responsible for the development of amyloid plaques and dementia in Alzheimer patients, PA may prove to be a useful memory-restorative agent. It would be worthwhile to explore the potential of this plant in the management of Alzheimer’s disease.     

Differences in morphine-induced antinociception in male and female offspring born of morphine exposed mothers

Objective:

Antinociceptive effect of morphine in offspring born of mothers that received saline or morphine during the gestation period was investigated.

Materials and Methods:

Wistar rats (200-250 g) received saline, morphine 0.5 mg/kg or 5 mg/kg during gestation days 14-16. All pups after weaning were isolated treatment/sex dependently and were allowed to fully mature. The antinociceptive effect of morphine was assessed in formalin test. Morphine (0.5-7.5 mg/kg) or saline (1 ml/kg) was injected intraperitoneally 10 min before formalin (50 μl of 2.5% solution in right hind-paw).

Results:

Male offspring born of saline-treated mothers were less morphine-sensitive than females. On the contrary, male offspring exposed prenatally to morphine (5 mg/kg) were more sensitive to morphine-induced antinociceptive response in formalin test. However, no difference in antinociceptive effect was observed amongst offspring of either sex born of mothers treated with morphine 0.5 mg/kg, identifying a lower dose effect of the opioid.

Conclusion:

The exposure to morphine during the developmental period may result in altered development of tolerance to morphine and thus involved in drug abuse.KEY WORDS: Formalin test, gestation, morphine, offspring, pain     

Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke,seizures and sensorimotor gating deficit

Background and purpose:

Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit.

Experimental approach:

3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit).

Key results:

Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801.

Conclusion and implications:

The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.     

Protective effect of Trigonella foenum-graecum Linn. on monosodium glutamate-induced dyslipidemia and oxidative stress in rats

Objectives:

The present study was designed to evaluate the effect of aqueous extract of Trigonella foenum-graecum(AqE-TFG) seeds on monosodium glutamate (MSG)-induced dyslipidemia and oxidative stress in Wistar rats.

Materials and Methods:

Neonatal Wistar rats were treated subcutaneously with MSG (4 g/kg b.w.) from day 2 to 14 after birth, on alternate days. After attaining six-weeks of age, MSG-treated rats were administered with AqE-TFG (0.5 and 1 g/kg b.w., orally) or orlistat (10 mg/kg b.w., orally) for 28 days, respectively. Serum chemistry and relevant enzymes in hepato-cardiac tissues were assessed on day 29.

Results:

AqE-TFG produced significant reduction in serum total cholesterol (TC), triglycerides (TGs), lactate dehydrogenase (LDH), aspartate amino transferase (AST), alanine amino transferase (ALT), hepatic and cardiac lipid peroxides (MDA) levels and elevation in serum high density lipoprotein cholesterol (HDL-C), hepatic and cardiac antioxidant enzymes [glutathione (GSH), and superoxide dismutase (SOD) and catalase (CAT)] levels.

Conclusion:

Results were comparable with orlistat, a standard anti-obesity drug, and provide clear evidence that the AqE-TFG treatment offered significant protection against MSG-induced dyslipidemia and oxidative stress, and may play an important role in amelioration of the free radical generated consequences like dyslipidemia and atherosclerosis.KEY WORDS: Antihyperlipidemic, monosodium glutamate, neonatal, oxidative stress, Trigonella foenum-graecum     

Effect of l-ornithine l-aspartate against thioacetamide-induced hepatic damage in rats

Objective:

To investigate the hepatoprotective activity of L-ornithine-L-aspartate against thioacetamide (TAA)-induced hepataopathy in rats.

Materials and Methods:

The hepatoprotective activity of L-ornithine-L-aspartate (OA) at a dose of 2 g/kg, p.o. for 10 days was evaluated against TAA (250 mg/kg, i.p. for 2 days) induced hepatopathy in rats. Biochemical parameters such as serum aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin and glutathione, thiobarbituric acid reactive substances, and protein in liver tissues were estimated to assess the liver function.

Results:

TAA-induced pathogenic changes in the levels of the above indices were significantly (P < 0.01) reversed by the OA treatment. OA treatment also exhibited significant restoration of the hepatic architecture and lobular structure in histological evaluation of the rat liver sections.

Conclusion:

Ornithine aspartate exhibited significant hepatoprotective activity against TAA-induced hepatic damage in rats.