The Role of Pre‐junctional D2‐like Receptors Mediating Quinpirole‐Induced Inhibition of the Vasodepressor Sensory CGRPergic Out‐flow in Pithed Rats

Calcitonin gene‐related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out‐flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D₁‐like and D₂‐like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre‐treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 μg/kg min.) followed by physiological saline (0.02 ml/min.), the D₁‐like receptor agonist SKF‐38393 (0.1–1 μg/kg min.) or the D₂‐like receptor agonist quinpirole (0.03–10 μg/kg min.). Under these conditions, electrical stimulation (0.56–5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T₉–T₁₂) resulted in frequency‐dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF‐38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 μg/kg min.). Moreover, the inhibition induced by 0.1 μg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous α‐CGRP; 0.1–1 μg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 μg/kg (i.v.) of the D₂‐like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D₂‐like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole‐induced inhibition of the vasodepressor sensory CGRPergic out‐flow is mainly mediated by pre‐junctional D₂‐like receptors.     

Specific Role of α2A‐ and α2B‐, but not α2C‐, Adrenoceptor Subtypes in the Inhibition of the Vasopressor Sympathetic Out‐flow in Diabetic Pithed Rats

Several lines of evidence have shown an association of diabetes with a catecholamines' aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, among other things, atypical actions of α₂‐adrenoceptor agonists within central and peripheral α₂‐adrenoceptors (e.g. profound antinociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the α₂‐adrenoceptor subtypes that inhibit the vasopressor sympathetic out‐flow in streptozotocin‐pre‐treated (diabetic) pithed rats. For this purpose, B‐HT 933 (up to 30 μg/kg min) was used as a selective α₂‐adrenoceptor agonist and rauwolscine as a non‐selective α_2A/2B/2C‐adrenoceptor antagonist; in addition, BRL 44408, imiloxan and JP‐1302 were used as subtype‐selective α_2A‐, α_2B‐ and α_2C‐adrenoceptor antagonists, respectively (all given i.v.). I.v. continuous infusions of B‐HT 933 inhibited the vasopressor responses induced by electrical sympathetic stimulation without affecting those by i.v. bolus injections of noradrenaline in both normoglycaemic and diabetic rats. Interestingly, the ED₅₀ for B‐HT 933 in diabetic rats (25 μg/kg min) was almost 1‐log unit greater than that in normoglycaemic rats (3 μg/kg.min). Moreover, the sympatho‐inhibition induced by 10 μg/kg min B‐HT 933 in diabetic rats was (i) abolished by 300 μg/kg rauwolscine or 100 and 300 μg/kg BRL 44408; (ii) partially blocked by 1000 μg/kg imiloxan; and (iii) unchanged by 1000 μg/kg JP‐1302. Our findings, taken together, suggest that B‐HT 933 has a less potent inhibitory effect on the sympathetic vasopressor responses in diabetic (compared to normoglycaemic) rats and that can probably be ascribed to a down‐regulation of α_2C‐adrenoceptors.     

Histamine H3 Receptors and Pharmacological Regulation of Their Functions (A Review)

Pharmaceutical Chemistry Journal -     

Role of Pre‐Junctional CB1, But not CB2, TRPV1 or GPR55 Receptors in Anandamide‐Induced Inhibition of the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats

Stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. Interestingly, endocannabinoids such as anandamide (which interacts with CB₁, CB₂, TRPV1 and GPR55 receptors) can regulate the activity of perivascular sensory nerves in dural blood vessels by modulating CGRP release. Yet, as no publication has reported whether this mechanism is operative in the healthy systemic vasculature, this study has specifically analysed the receptors mediating the potential inhibitory effects of the cannabinoid (CB) receptor agonists anandamide (non‐selective), JWH‐015 (CB₂) and lysophosphatidylinositol (GPR55) on the rat vasodepressor sensory CGRPergic outflow (an index of systemic vasodilatation). Healthy pithed rats were pre‐treated with consecutive i.v. continuous infusions of hexamethonium, methoxamine and the above agonists. Electrical spinal (T₉–T₁₂) stimulation of the vasodepressor sensory CGRPergic outflow or i.v. injections of α–CGRP produced frequency‐dependent or dose‐dependent vasodepressor responses. The infusions of anandamide in a dose‐dependent manner inhibited the vasodepressor responses by electrical stimulation (remaining unaffected by JWH‐015 or lysophosphatidylinositol), but not those by α–CGRP. After i.v. administration of antagonists, the inhibition by 3.1 μg/kg min anandamide was: (i) potently blocked by 31–100 μg/kg NIDA41020 (CB₁), (ii) unaffected by 180 μg/kg AM630 (CB₂), 31 μg/kg cannabidiol (GPR55) or 31–100 μg/kg capsazepine (TRPV1) and (iii) slightly blocked by 310 μg/kg AM630. The above doses of antagonists were enough to block their respective receptors. These results suggest that anandamide‐induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by pre‐junctional activation of CB₁ receptors, with no pharmacological evidence for the role of CB₂, TRPV1 or GPR55 receptors.     

Cardiovascular Alterations during the Interictal Period in Awake and Pithed Amygdala‐Kindled Rats

Epileptic seizures are often accompanied by increased sympathetic cardiovascular activity (even interictally), but it remains unknown whether this increased activity is of central and/or peripheral origin. Hence, this study investigated the cardiovascular alterations produced by amygdala kindling in awake and pithed Wistar rats. Blood pressure (BP) and heart rate (HR) were initially recorded by tail cuff plethysmography in awake control, sham‐operated and amygdala‐kindled rats before and 24 hr after the kindling process. The after‐discharge threshold (ADT) was measured under different conditions to correlate brain excitability with BP and HR in kindled rats. Twenty‐four hours after the last kindling seizure, (i) HR, systolic and diastolic BP were increased and (ii) only higher HR values correlated with lower ADT values. Forty‐eight hr after the last kindled seizure, all rats were pithed and prepared for analysing the tachycardic, vasopressor and vasodepressor responses by (i) stimulation of the sympathetic or sensory vasodepressor CGRPergic out‐flows (stimulus–response curves, S‐R curves) and (ii) intravenous injections of noradrenaline or α‐CGRP (dose–response curves, D‐R curves). Interestingly, (i) the tachycardic S‐R and D‐R curves were attenuated, whilst the CGRPergic S‐R and D‐R curves were potentiated in kindled rats, and (ii) the vasopressor noradrenergic S‐R and D‐R curves were not significantly different in all groups. Therefore, the kindling process may be associated with overstimulation in the central sympathetic and sensory out‐flows interictally, producing (i) peripheral attenuation of cardiac sympathetic out‐flow and β‐adrenoceptor activity and (ii) peripheral potentiation of vasodepressor sensory CGRPergic out‐flow and CGRP receptor activity.     

Treatment with Dehydroepiandrosterone Increases Peripheral Benzodiazepine Receptors of Mitochondria from Cerebral Cortex in d‐Galactose‐Induced Aged Rats

Abstract: The aim of this study was to determine whether dehydroepiandrosterone (DHEA) could regulate the expression of peripheral benzodiazepine receptors of mitochondria in cerebral cortex. The rats were divided into five groups. Those, in the vehicle‐physiological or senescent group, received physiological or d ‐galactose (subcutaneously) once a day. Rats, in the vehicle‐dimethyl sulfoxide‐ or DHEA‐treated senescent group, received 2% of dimethyl sulfoxide or DHEA (intraperitoneally) every other day besides d ‐galactose (subcutaneously) once a day. Rats in the DHEA‐treated normal group received physiological once a day and DHEA every other day. After 8‐week, spatial learning was assessed for 5 days by water maze methods. Following behavioural testing, the cerebral cortex mitochondria were purified for PK11195 binding analysis. When compared to the respective vehicle, d ‐galactose alone induced a significant impairment in water maze performance accompanied by a reduction (30.7%) in peripheral benzodiazepine receptor density of mitochondria, and DHEA displayed a significant enhancement in learning memory accompanied by the elevation (18.3%) of peripheral benzodiazepine receptor density but not affinity in senescent rats. DHEA showed insignificant effects on both learning/memory ability and peripheral benzodiazepine receptors in normal rats when compared to physiological saline. These results suggest that chronic treatment with DHEA enhance cognitive function and increase peripheral benzodiazepine receptor density in cerebral cortex mitochondria in middle‐aged senescent rats.     

Evidence against the Participation of μ- and κ-Opioid Receptors in the Analgesic Activity of Ketorolac in Rats

The possibility that activation of opioid receptors is involved in the analgesic activity of ketorolac was explored. The analgesic effects of ketorolac, of ketocyclazocine, the prototype κ-agonist, and of morphine, the prototype μ-agonist, were assayed in the pain-induced functional impairment model in the rat. All three drugs induced a significant analgesic effect in this model. Naloxone was able to antagonize the effects of ketocyclazocine and morphine. However, the effect of ketorolac was not blocked by naloxone, although a high dose, 3·2 mg kg^?1, capable of blocking κ-receptors was used. It is concluded that activation of μ- or κ-opioid receptors, by either a direct or an indirect mechanism, does not play a role in the analgesic activity of ketorolac.     

The Disposition of Thioperamide,a Histamine H3-Receptor Antagonist,in Rats

Abstract— An HPLC method using an ovomucoid-conjugated column has been developed for measurement of thioperamide, a histamine H₃ antagonist, with a minimum quantitation limit of 0·05 μg mL^?1 The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg^?1), the plasma concentration decreased monoexponentially with a half-life of 26·9 min. The apparent total body clearance of thioperamide from rat plasma was 74·6 mL min^?1 kg^?1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.     

Apomorphine‐Induced Aggressive Behaviour in para‐Chlorophenylalanine‐Treated Male Rats: Implications to Brain [3H]Ketanserin Binding and Monoamine Content

Abstract: The aim of this study was to investigate the role of serotoninergic neurotransmission and the effect of acute para‐chlorophenylalanine (350 mg/kg, intraperitoneally) treatment on apomorphine‐induced aggressive behaviour in adult male Wistar rats. In addition, [³H]ketanserin binding and monoamine content were studied. Repeated administration of apomorphine (1.0 mg/kg, subcutaneously, once daily for two weeks) gradually induced aggressive behaviour. Acute p‐chlorophenylalanine treatment down‐regulated the [³H]ketanserin binding and reduced over 90 per cent the content of serotonin and 5‐hydroxyindolacetic acid. In a half of the p‐chlorophenylalanine‐treated animals, the aggressive behaviour was suppressed, while there was no difference in [³H]ketanserin binding or monoamine content between the p‐chlorophenylalanine treated aggressive and non‐aggressive animals. In conclusion, the acute p‐chlorophenylalanine treatment attenuates the aggressiveness only in half of the animals, while the latter phenomenon is independent on the CNS monoamine content or [³H]ketanserin binding.     

The Disposition of (R)-α-Methylhistamine,a Histamine H3-Receptor Agonist,in Rats

Abstract— Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-α-methylhistamine (α-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of α-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12·6 mg kg^?1), the plasma concentration declined biexponentially with a half-life of 1·3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 μg min mL^?1 and 97 mL min^?1 kg^?1, respectively. After administration, α-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of α-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that α-methylhistamine crosses the blood-brain barrier in rats with difficulty.     

Dose Response of Carboplatin‐Induced Nephrotoxicity in Rats

Abstract: Carboplatin, a second‐generation platinum‐containing anticancer drug, is currently being used against a variety of cancers. High‐dose carboplatin chemotherapy can cause renal tubular injury in cancer patients. However, the biochemical mechanism of carboplatin‐induced renal injury has not been well studied. This study investigated the dose response of carboplatin‐induced changes in endogenous antioxidants, lipid peroxidation and platinum content in rat kidney. Male Wistar rats (250–300 g) were divided into five groups and treated as follows: (1) control (saline, intraperitoneally); (2) carboplatin (64 mg/kg, intraperitoneally); (3) carboplatin (128 mg/kg, intraperitoneally); (4) carboplatin (192 mg/kg, intraperitoneally); and (5) carboplatin (256 mg/kg, intraperitoneally). The animals were sacrificed four days after treatment. The blood and kidneys were isolated and analyzed. Plasma creatinine and blood urea nitrogen levels were increased significantly in response to carboplatin in a dose‐dependent manner. Renal superoxide dismutase and catalase activities were decreased significantly due to carboplatin at dosages of 128 mg/kg and above. The protein expressions of renal copper/zinc‐superoxide dismutase and manganese‐superoxide dismutase significantly depleted after carboplatin. Carboplatin (192 and 256 mg/kg) significantly increased lipid peroxidation (malondialdehyde concentration) in rat kidneys. Carboplatin dose‐dependently increased the renal platinum concentration, with significance at dosages of 128 mg/kg and above. Carboplatin (256 mg/kg) significantly increased renal xanthine oxidase activity, while ratio of reduced to oxidized glutathione depleted significantly. The data suggested that carboplatin caused dose‐dependent oxidative renal injury, as evidenced by renal antioxidant depletion, enhanced lipid peroxidation, platinum content, plasma creatinine and blood urea nitrogen levels in rats.     

3‐Keto‐1,5‐bisphosphonates Alleviate Serum‐Oxidative Stress in the High‐fat Diet Induced Obesity in Rats

Obesity has become a leading global health problem owing to its strong association with a high incidence of oxidative stress. Many epidemiologic studies showed that an antioxidant supplementation decreases the state of oxidative stress. In the present work, a HFD ‐induced rat obesity and oxidative stress were used to investigate the link between fat deposition and serum‐oxidative stress markers. We also studied the effect of a chronic administration of 3‐keto‐1,5‐bisphosphonates 1 (a & b) (40 μg/kg/8 weeks/i.p.). Exposure of rats to HFD during 16 weeks induced fat deposition, weight gain and metabolic disruption characterized by an increase in cholesterol, triglyceride and glycemia levels, and a decrease in ionizable calcium and free iron concentrations. HFD also induced serum‐oxidative stress status vocalized by an increase in ROS ( H ₂ O ₂ ), MDA and PC levels, with a decrease in antioxidant enzyme activity ( CAT , GP x , SOD ). Importantly, 3‐keto‐1,5‐bisphosphonates corrected all the deleterious effects of HFD treatment in vivo, but it failed to inhibit lipases in vitro and in vivo. These studies suggest that 3‐keto‐1,5‐bisphosphonates 1 could be considered as safe antioxidant agents that should also find other potential biological applications.     

Impact of the Chronic Omega‐3 Fatty Acids Supplementation in Hemiparkinsonism Model Induced by 6‐Hydroxydopamine in Rats

Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega‐3 polyunsaturated fatty acids (ω‐3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In this study, the protective effect of ω‐3 PUFA administration on the 6‐hydroxydopamine (6‐OHDA) model of PD in rats was investigated. ω‐3 PUFA (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6‐OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω‐3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acid levels on the striatum from hemiparkinsonian rats, followed by reduction in the number of apomorphine‐induced rotations and promotion of a partial locomotor recovery. In addition, ω‐3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, this study suggests that supplementation with ω‐3 PUFAs prevents behavioural and neurochemical disturbances induced by 6‐OHDA, presenting a potential neuroprotective action.     

Evidence for Functional δ-Opiate Receptors in the Rat Intestine

Abstract— The selective δ-opiate agonists d -Ser², Leu⁵, Thr⁶-enkephalin (DSLET), d -Ala², d -Leu⁵-enkephalin and d -Pen², d -Pen⁵-enkephalin caused inhibition of the cholinergic contraction produced by transmural stimulation of the rat isolated jejunum. Dynorphin A, which is an agonist at both κ- and δ-opioid receptors also inhibited the cholinergic contraction, as did leu- and met-enkephalin. The selective μ-receptor agonist d -Ala²-NMe-Phe⁴, Gly-ol⁵-enkephalin was the least potent of all peptides tested. In general, the order of potency of the peptides was similar to that reported for the δ-receptor-rich mouse vas deferens with potency values similar to those recorded previously for the hamster vas deferens. The selective δ-opioid antagonist naltrindole caused parallel shifts to the concentration-effect curve to DSLET giving a pA₂ value of 10·15. The results indicate that the previously identified δ-binding sites in the rat jejunum may correspond to functional δ-opiate receptors involved in attenuating acetylcholine release.     

Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats

In this study, we evaluated the effect of an analogue of l ‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l ‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l ‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l ‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l ‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l ‐carnitine and improves the pharmacological profile of l ‐carnitine.     

Effects of Anticonvulsants on Local Anaesthetic‐Induced Neurotoxicity in Rats

Abstract: The effects of various anticonvulsants on local anaesthetics procaine‐ and lidocaine‐induced convulsions were investigated in rats. Pretreatment with diazepam (2.5–5 mg/kg, intraperitoneally) and clonazepam (5–10 mg/kg, intraperitoneally) completely protected the rats against both local anaesthetic‐induced convulsions. Phenobarbital (12.5–50 mg/kg, subcutaneously) also significantly decreased the incidence of both convulsions and prolonged their latencies. Carbabazepine (10–40 mg/kg, intraperitoneally) did not completely repress both convulsions, but it prolonged their latencies. Phenytoin (5–20 mg/kg, intraperitoneally) and primidone (30–60 mg/kg, intraperitoneally) markedly enhanced both local anaesthetic‐induced convulsions, as shown by shortening of latency and increase in mortality. Valproate (100–200 mg/kg, intraperitoneally) produced a protective effect against procaine‐induced convulsions, while it strongly enhanced lidocaine‐induced convulsions. These results suggest that the benzodiazepines are effective drugs to prevent neurotoxicity induced by local anaesthetics, while phenytoin and primidone potentiate them.     

Gastroprotective Effect of Rutin against Indomethacin‐Induced Ulcers in Rats

Abstract: Several reports have indicated that indomethacin‐induced gastropathy is mediated through generation of free radicals, neutrophil infiltration and disturbance in nitric oxide production. Rutin is a potent antioxidant flavonoid. Recently, rutin was reported to inhibit neutrophil infiltration and to modulate nitric oxide production in gastric mucosa. Therefore, the aim of this study was to investigate the protective effect of rutin against indomethacin‐induced gastric injury. Accordingly, four groups of rats were used. The first three groups were injected orally with vehicle, rutin (200 mg/kg) and indomethacin (48 mg/kg) respectively. The fourth group was injected with rutin 1 hr before indomethacin. Animals were killed after 6 hr of indomethacin administration. Gastric juice acidity and gastric injury were evaluated directly. Moreover, the activities of myeloperoxidase, superoxide dismutase and the contents of reduced glutathione, thiobarbituric acid reactive substance and total nitrite/nitrate (as a marker of nitric oxide production) were determined in mucosal tissues. Indomethacin increased gastric ulcer index, gastric myeloperoxidase activity, gastric acidity and thiobarbituric acid reactive substance contents compared with control. On the other hand, indomethacin decreased glutathione, nitrite/nitrate contents and superoxide dismutase activity. Histopathological examination of the stomachs of indomethacin‐treated rats revealed degenerative changes in gastric tissues. Pre‐treatment with rutin protected gastric tissues against indomethacin‐induced gastropathy as demonstrated from reduction in the ulcer index, attenuation of histopathological changes and amelioration of the altered oxidative stress and biochemical parameters. These results indicate that rutin has a protective effect against indomethacin‐induced gastropathy probably through inhibiting neutrophil infiltration, suppression of oxidative stress generation and replenishing nitrite/nitrate levels regardless of gastric acidity.     

Polyamine and Redox Modulation of [3H]MK‐801 Binding to N‐Methyl‐d‐aspartate Receptors in the Spinal Cord and Cerebral Cortex

Abstract: The pharmacology of N‐methyl‐d ‐aspartate (NMDA) receptors shows regional differences in affinity for various agonists and antagonists. We have investigated the modulatory mechanisms acting via the polyamine, redox and proton sites in the cerebral cortex and the spinal cord of adult, male rats using [³H]MK‐801 binding. The affinity for glycine‐independent spermine stimulation was one magnitude higher in cerebrocortical than in spinal cord membranes while the affinity for the spermine antagonist arcaine was similar. Spermine abolished the inhibiting effect of low pH in both regions. Thus, the difference in the polyamine site between the two regions seems to be restricted to agonist binding. The proportion of high affinity/total ifenprodil binding was ≈35% both in the spinal cord and the cerebral cortex, suggesting similar relative amounts of the NMDA receptor subunit 2B. The affinity of ifenprodil to the high affinity site was however significantly higher in the cerebral cortex. Redox modulatory agents had similar effects in the two regions but spermine fully counteracted the inhibiting effect of 0.2 mM 5,5′‐dithio‐bis(2‐nitrobenzoic acid) (DTNB) in the cerebral cortex while there was only a partial effect in the spinal cord. These data show that the regional pharmacological heterogeneity involves several of the mechanisms regulating the function of the NMDA receptor. The data also indicate that the NMDA receptor subunit 2B is much more common in spinal cord than previously suggested.     

Protective Effect of Sesamol against 3‐Nitropropionic Acid‐Induced Cognitive Dysfunction and Altered Glutathione Redox Balance in Rats

Abstract: Sesamol (SML) (Sesamum indicum, Linn, Pedaliaceae) has been used traditionally as a health supplement in India and other countries for a long time. It is a well‐known antioxidant, currently being tried against several neurological disorders. The present study was designed to evaluate the potential of sesamol treatment against 3‐nitropropionic acid (3‐NP)‐induced cognitive impairment and oxidative damage in striatal, cortex and hippocampal regions of the rat. The memory performance was assessed by Morris water maze and elevated plus maze paradigms. The oxidative damage was assessed by estimating the total glutathione, reduced glutathione, oxidized glutathione levels and glutathione redox ratio. Glutathione‐S‐transferase and lactate dehydrogenase enzymes were also measured in different brain areas. 3‐NP significantly impaired memory performance as assessed in Morris water maze and elevated plus maze, which was significantly attenuated by sesamol (5, 10 and 20 mg/kg) pre‐treatment. On the other hand, 3‐NP significantly induced oxidative stress and depleted total glutathione, reduced glutathione, glutathione‐S‐transferase, lactate dehydrogenase enzyme levels and redox ratio in the striatum, cortex and hippocampal regions as compared to the vehicle‐treated group. Sesamol pre‐treatment restored oxidative defence possibly by its free radical scavenging activity as compared to the 3NP‐treated group. The present study suggests that sesamol could be used as an effective agent in the management of Huntington’s disease.