(S)-[18F]THK5117 brain uptake is associated with Aß plaques and MAO-B enzyme in a mouse model of Alzheimer's disease.

The mouse model of beta-amyloid (Aß) deposition, APP/PS1-21, exhibits high brain uptake of the tau-tracer (S)-[18F]THK5117, although no neurofibrillary tangles are present in this mouse model. For this reason we investigated (S)-[18F]THK5117 off-target binding to Aß plaques and MAO-B enzyme in APP/PS1-21 transgenic (TG) mouse model of Aß deposition. APP/PS1-21 TG and wild-type (WT) control mice in four different age groups (2-26 months) were imaged antemortem by positron emission tomography with (S)-[18F]THK5117, and then brain autoradiography. Additional animals were used for immunohistochemical staining and MAO-B enzyme blocking study with deprenyl pre-treatment. Regional standardized uptake value ratios for the cerebellum revealed a significant temporal increase in (S)-[18F]THK5117 uptake in aged TG, but not WT, brain. Immunohistochemical staining revealed a similar increase in Aß plaques but not endogenous hyper-phosphorylated tau or MAO-B enzyme, and ex vivo autography showed that uptake of (S)-[18F]THK5117 co-localized with the amyloid pathology. Deprenyl hydrochloride pre-treatment reduced the binding of (S)-[18F]THK5117 in the neocortex, hippocampus, and thalamus. This study's findings suggest that increased (S)-[18F]THK5117 binding in aging APP/PS1-21 TG mice is mainly due to increasing Aß deposition, and to a lesser extent binding to MAO-B enzyme, but not hyper-phosphorylated tau.

Selegiline (L-Deprenyl) Mitigated Oxidative Stress, Cognitive Abnormalities, and Histopathological Change in Rats: Alternative Therapy in Transient Global Ischemia.

Selegiline (L-deprenyl) is the major drug which is used in the treatment of Parkinson's disease because of its neurotrophic and antiapoptotic properties. Previous studies suggested that low dose of L-methamphetamine (L-METH) caused lower mortality rate in patients with severe traumatic brain injury. As L-methamphetamine is one of the metabolites of selegiline, the present study aims to examine whether L-deprenyl can improve cognitive, biochemical, and histopathological injury in animal model of transient global ischemia. The animals were randomized in ten groups orally gavaged three times a week for 28 days. Then, novel object recognition (NOR) was conducted to assess their behavioral abnormality. After scarification of the rats, their brains were divided into two sections to measure oxidative stress parameters and perform pathological evaluations in rats. Our data revealed the involvement of oxidative stress, behavioral despair, and pathological data in transient global ischemia rats. Significant recovery in cognitive behavior, oxidative stress biomarker, and number of dead cell in histopathological assay was observed in rats treated with 1,2 and 4 mg/kg of selegiline. So, selegiline appears to be useful in alternative therapy of transient global ischemia.

Rasagiline and selegiline modulate mitochondrial homeostasis, intervene apoptosis system and mitigate α-synuclein cytotoxicity in disease-modifying therapy for Parkinson's disease.

Parkinson's disease has been considered as a motor neuron disease with dopamine (DA) deficit caused by neuronal loss in the substantia nigra, but now proposed as a multi-system disorder associated with α-synuclein accumulation in neuronal and non-neuronal systems. Neuroprotection in Parkinson's disease has intended to halt or reverse cell death of nigro-striatal DA neurons and prevent the disease progression, but clinical studies have not presented enough beneficial results, except the trial of rasagiline by delayed start design at low dose of 1 mg/day only. Now strategy of disease-modifying therapy should be reconsidered taking consideration of accumulation and toxicity of α-synuclein preceding the manifest of motor symptoms. Hitherto neuroprotective therapy has been aimed to mitigate non-specific risk factors; oxidative stress, mitochondrial dysfunction, apoptosis, deficits of neurotrophic factors (NTFs), inflammation and accumulation of pathogenic protein. Future disease-modify therapy should target more specified pathogenic factors, including deregulated mitochondrial homeostasis, deficit of NTFs and α-synuclein toxicity. Selegiline and rasagiline, inhibitors of type B monoamine oxidase, have been proved to exhibit potent neuroprotective function: regulation of mitochondrial apoptosis system, maintenance of mitochondrial function, increased expression of genes coding antioxidant enzymes, anti-apoptotic Bcl-2 and pro-survival NTFs, and suppression of oligomerization and aggregation of α-synuclein and the toxicity in cellular and animal experiments. However, the present available pharmacological therapy starts too late to reverse disease progression, and future disease-modifying therapy should include also non-pharmacological complementary therapy during the prodromal stage.

Brain region specific methylation and Sirt1 binding changes in MAOA promoter is associated with sexual dimorphism in early life stress induced aggressive behavior.

The maladaptive form of aggressive behavior confers risk for violence and criminal incidences with profound impact on society. Although considerable research has been devoted to elucidate the etiology of aggression, molecular correlates of sex differences remains largely unexplored. Also, little attention has been given to whether males and females respond differently to similar causal factor of aggression. Here, we show the possible association of brain region specific neural activity (c-Fos expression) and monoamine oxidase A (MAOA) epigenetic state with sexual dimorphism in peripubertal stress (PPS) induced adulthood aggression. While PPS adult males exhibited escalated aggression, females spent maximal time in social exploration. c-Fos expression was brain region and sex specific. In the PPS adult cohort, only males showed elevated c-Fos expression in the prefrontal cortex, indicative of their hyper-responsive behavior. MAOA expression and enzyme activity was reduced in hypothalamus and increased in prefrontal cortex of hyper-aggressive male mice. Investigation into the underlying mechanisms revealed hypomethylation in prefrontal cortex and hypermethylation in hypothalamus of MAOA promoter negatively correlating with the expression pattern. On the other hand, binding of Sirt1 to MAOA promoter was diametrically opposite being increased in prefrontal cortex and reduced in hypothalamus. In females, neither expression nor epigenetic state of MAOA gene was significantly altered between control and PPS adult mice. Our study revealed novel epigenetic correlates of sexual dimorphism in stress induced aggressive psychopathology. However, given the multi-factorial nature with environmental influences, further studies are warranted to uncover the biological hub.

Effects of low and high deprenyl dose on antioxidant enzyme activities in the adult rat brain.

We evaluated the effects of low dose deprenyl (LDD, 0.0025 mg/kg per day) and high dose deprenyl (HDD, 0.25 mg/kg per day) treatment of male Wistar rats for 30 days on the activities of SOD and CAT in the cortex, striatum, and hippocampus. Total SOD and MnSOD activities were increased with LDD (p <0.05) in the cortex (0.74 ± 0.03; 0.31 ± 0.02), striatum (0.75 ± 0.02; 0.27 ± 0.03) and CA1 region of the hippocampus (0.75 ± 0.02; 0.29 ± 0.03) compared to the control (0.53 ± 0.02; 0.15 ± 0.02), but reduced (p <0.05) with HDD compared to the LDD group. CAT activity was increased (p <0.05) with LDD in the cortex (27.34 ± 3.11), striatum (22.22 ± 1.85), and hippocampal CA1 region (16.62 ± 2.15) compared to control (10.33 ± 1.01), while a decrease was induced by HDD in the striatum (9.85 ± 1.09) compared to LDD. There was a significant (p <0.05) difference in number of Fluoro Jade B positive CA1 neurons induced by LDD (21.14 ± 2.85%) and HDD (12.61 ± 1.42%), as well as the number of NeuN positive CA1 neurons after LDD (183.35 ± 11.14 cells/mm) and HDD (238.45 ± 14.11 cells/mm (p < 0.05). Deprenyl showed a potential in improving the neurological outcome and reducing the oxidative damage.

The effect of R-(-)-deprenyl administration on antioxidant enzymes in rat testis.

The aim of the study was to investigate the effect of R-(-)-deprenyl administration on the activity and localization of superoxide dismutases (SODs) and catalase (CAT) in rat testis. After 30 days of intraperitoneal administration of either saline (control) or R-(-)-deprenyl dissolved in saline at concentrations of 0.0025mg/kg (low dose of deprenyl, LDD) or 0.25mg/kg (high dose of deprenyl, HDD), males were killed by thiopental, and their testes were collected. We found that deprenyl administration significantly increased the activity of antioxidant enzymes, and this effect varied by dosage. LDD caused significant elevation of all monitored enzymes, but HDD did not increase the activity of SOD2. Employing immunohistochemistry, we detected enzymes predominantly in Leydig cells (SOD1, SOD2, CAT), in late spermatids and residual bodies (SOD1, SOD2), and in primary spermatocytes (SOD2). Histopathological examination did not reveal testicular damage in experimental groups compared to control. Deprenyl proved to be a potent stimulator of antioxidant enzymes in rat testes; therefore, it could be used in the therapy of male infertility. On the other hand, it is crucial to choose a proper dose, since lower dose was more competent compared to a dosage that was one hundred times higher.

Pharmacological evaluation of nasal delivery of selegiline hydrochloride-loaded thiolated chitosan nanoparticles for the treatment of depression.

The aim of the present study was to investigate the propensity of thiolated chitosan nanoparticles (TCNs) to enhance the nasal delivery of selegiline hydrochloride. TCNs were synthesized by the ionic gelation method. The particle size distribution (PDI), entrapment efficiency (EE), and zeta potential of modified chitosan (CS) nanoparticles were found to be 215 ± 34.71 nm, 70 ± 2.71%, and + 17.06 mV, respectively. The forced swim and the tail suspension tests were used to evaluate the anti-depressant activity, in which elevated immobility time was found to reduce on treatment. TCNs seem to be promising candidates for nose-to-brain delivery in the evaluation of antidepressant activity.

The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.

Antidepressant-like effect of Ilex paraguariensis in rats.

In this study, we investigated the possible antidepressant-like effect of I. paraguariensis in rats. Rats were treated for four weeks with an aqueous extract of I. paraguariensis in drinking water, following the traditional preparation of this beverage. After the period of treatment, behavioral (elevated plus-maze, open field test, and forced swimming test) and biochemical parameters (lipid peroxidation assay, thiol content, vitamin C levels, and monoamine oxidase activity) were evaluated. Animals were also analyzed on forced swimming test after 24 hours of I. paraguariensis intake. An additional group was injected with selegiline 24 hours and 30 minutes before forced swimming test as positive control. HPLC analysis revealed the profile of I. paraguariensis extract. I. paraguariensis reduced the immobility time on forced swimming test without significant changes in locomotor activity in the open field test. Any anxiolytic/anxiogenic effect of I. paraguariensis was observed in rats through the elevated plus-maze test. The antidepressant-like effect of I. paraguariensis was not accompanied by inhibitory effect on monoamine oxidase activity. There were no significant alterations on lipid peroxidation, thiol content, and vitamin C levels among the groups. In conclusion, aqueous extract of I. paraguariensis decreases the time of immobility in rats suggesting an antidepressant-like effect.

Bacopa monnieri and L-deprenyl differentially enhance the activities of antioxidant enzymes and the expression of tyrosine hydroxylase and nerve growth factor via ERK 1/2 and NF-κB pathways in the spleen of female wistar rats.

Aging is characterized by development of diseases and cancer due to loss of central and peripheral neuroendocrine-immune responses. Free radicals exert deleterious effects on neural-immune functions in the brain, heart, and lymphoid organs and thus, affecting the health. Bacopa monnieri (brahmi), an Ayurvedic herb, and L-deprenyl, a monoamine oxidase-B inhibitor, have been widely used in the treatment of neurodegenerative diseases. The purpose of this study was to investigate whether brahmi (10 and 40 mg/kg BW) and deprenyl (1 and 2.5 mg/kg BW) treatment of 3-month old female Wistar rats for 10 days can modulate the activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)] in the brain and spleen. In addition, the effects of these compounds on the expression of tyrosine hydroxylase (TH), nerve growth factor (NGF), the intracellular signaling markers, p-ERK1/2, p-CREB, and p-NF-kB, and nitric oxide (NO) production were measured in the spleen by Western blot analysis. Both brahmi and deprenyl enhanced CAT activity, and p-TH, NGF, and p-NF-kB expression in the spleen. However, deprenyl alone was found to enhance the p-ERK1/2 and p-CREB expression in the spleen. The activities of SOD, CAT, and GPx in the thymus, mesenteric lymph nodes, heart, and brain areas (frontal cortex, medial basal hypothalamus, striatum, and hippocampus) were differentially altered by brahmi and deprenyl. Brahmi alone enhanced NO production in the spleen. Taken together, these results suggest that both brahmi and deprenyl can protect the central and peripheral neuronal systems through their unique effects on the antioxidant enzyme activities and intracellular signaling pathways.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroblastic apoptosis in the subventricular zone is caused by 1-methy-4-phenylpiridinium (MPP(+)) converted from MPTP through MAO-B.

Intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration induces apoptosis of subventricular zone (SVZ) doublecortin (Dcx)-positive neural progenitor cells (migrating neuroblasts, A cells). Actually, a metabolite of MPTP, 1-methy-4-phenylpiridinium (MPP(+)), is responsible for neural progenitor cell toxicity. In the present study, to examine whether the MPTP-induced SVZ cell apoptosis is caused directly by MPP(+) metabolized through monoamine oxidase B (MAO-B), MPTP or MPP(+) was intracerebroventricularly (icv) injected into C57BL/6 mice. At Day 1 postinjection, many terminal deoxynucleotidyl transferase-mediated dUTP endlabeling (TUNEL)-positive cells were observed in the SVZ of both low (36 µg) and high (162 µg) dose MPTP- and MPP(+)-injected mice. The number of Dcx-positive A cells showed a significant decrease following high dose of MPTP- or MPP(+)-injection on Days 1 and 3, respectively, whereas that of EGFR-positive C cells showed no change in mice with any treatment. In addition, prior icv injection of a MAO-B inhibitor, R(-)-deprenyl (deprenyl), inhibited MPTP-induced apoptosis, but not MPP(+)-induced apoptosis. MAO-B- and GFAP-double positive cells were detected in the ependyma and SVZ in all mice. It is revealed from these results that icv injection of MPTP induces apoptosis of neural progenitor cells (A cells) in the SVZ via MPP(+) toxicity. In addition, it is suggested that the conversion from MPTP to MPP(+) is caused mainly by MAO-B located in ependymal cells and GFAP-positive cells in the SVZ.

PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice.

Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [(11)C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and l-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD.

Supplementation of deprenyl attenuates age associated alterations in rat cerebellum.

Aging, a multifactorial process of enormous complexity is characterised by physio-chemical and biological aspects of cellular functions. It is closely associated with changes in metabolism of various biological molecules in the system. In the present study, we have investigated the effect of deprenyl on cerebellum during ageing process in male Wistar rats with respect to the changes in levels of protein, glycoproteins and amino acids in experimental rats of three age groups (6, 12 and 18 months old). Intraperitoneal administration of liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p., significantly P < 0.05) attenuated age-associated alterations in the levels of amino acids (taurine, aspartate, glutamate, arginine, hydroxy proline and homocysteine), protein content and glycoprotein components (hexose and hexosamine) in the rat cerebellum. The results of the present investigation indicate that the protective effect of deprenyl is probably related to its ability to strengthen the neuronal membrane by its membrane stabilizing action or to a counteraction of free radicals by its antioxidant property.

Bacopa monniera prevents from aluminium neurotoxicity in the cerebral cortex of rat brain.

Bacopa monniera is a perennial herb, and is used as a nerve tonic in äyurveda, a traditional medicinal system in India. Aluminium-induced neurotoxicity is well known and different salts of aluminium have been reported to accelerate oxidative damage to biomolecules like lipids, proteins and nucleic acids. The objective of the present study was to investigate whether Bacopa monniera could potentially inhibit aluminium toxicity in the cerebral cortex. Male Wister rats (8 months old) were administered with AlCl(3) orally at a dose of 50mg/kg/day in drinking water for 1 month. Experimental rats were given AlCl(3) along with Bacopa monniera extract at a dose of 40 mg/kg/day. One group of rats was treated with l-deprenyl at a dose of 1mg/kg/day along with AlCl(3) treatment. We have observed that Bacopa monniera prevented accumulation of lipid and protein damage significantly, which resulted from aluminium intake. Decline in the activity of endogenous antioxidant enzymes associated with aluminium administration was also inhibited by Bacopa monniera extract. The potential of Bacopa monniera to inhibit Al-induced oxidative stress was observed to be similar to that of l-deprenyl, which was taken as standard. The potential of Bacopa monniera extract to prevent aluminium neurotoxicity was reflected at the microscopic level as well, indicative of its neuroprotective effects. These findings strongly implicate that Bacopa monniera has potential to protect brain from oxidative damage resulting from aluminium toxicity.

High-throughput screening for monoamine oxidase-A and monoamine oxidase-B inhibitors using one-step fluorescence assay.

AIM: To develop high-throughput screening (HTS) assays for monoamine oxidase (MAO)-A and MAO-B inhibitors. METHODS: A fluorescence probe based method measuring MAO-A and MAO-B activity was established and optimized, with its sensitivity, stability and specificity evaluated. Reaction conditions including enzyme sources, substrate concentrations, incubation volume and reaction time in 384-well format were optimized to achieve sensitive and low consumptive goal. RESULTS: In optimized conditions, dynamic parameters of MAO-A and MAO-B were obtained. The K(m) value of serotonin to MAO-A was 1.66 micromol/L, while that of benzylamine to MAO-B was 0.80 micromol/L. The IC(50) value of clorgyline to MAO-A was 2.99 nmol/L, and that of deprenyl to MAO-B was 7.04 nmol/L, matching those obtained from traditional spectrometric assays. Among tested samples, one compound exerted an inhibitory effect on MAO-A activity with IC(50) as 0.36 micromol/L, and three compounds had an inhibitory effect on MAO-B activity with IC(50) as 0.13, 0.19, and 0.13 micromol/L. The Z' factor was 0.71+/-0.03 and 0.75+/-0.03 in MAO-A-inhibitor and MAO-B-inhibitor HTS system, respectively. CONCLUSION: The established assays can be well applied to MAO-A and MAO-B inhibitor screening with high quality, precision and reproducibility.

Neuroprotective role of Bacopa monniera extract against aluminium-induced oxidative stress in the hippocampus of rat brain.

Bacopa monniera is a nerve tonic used extensively in traditional Indian medicinal system "Ayurveda". Reports regarding its various antioxidative, adaptogenic and memory enhancing roles have already appeared in the last few decades. In the present study, aluminium chloride (AlCl(3)) was used to generate neurotoxicity. We have investigated the neuroprotective effect of Bacopa extract against aluminium-induced changes in peroxidative products, such as thio-barbituric acid-reactive substance (TBA-RS) and protein carbonyl contents and superoxide dismutase (SOD) activity. Effect on lipofuscin (age pigments) accumulation and ultrastructural changes were also studied. Bacopa effects were compared with those of l-deprenyl. Co-administration of Bacopa extract during aluminium treatment significantly prevented the aluminium-induced decrease in SOD activity as well as the increased oxidative damage to lipids and proteins. Protective effect was also observed at microscopic level. Fluorescence and electron microscopic studies revealed considerable inhibition of intraneuronal lipofuscin accumulation and necrotic alteration in the CA1 region of the hippocampus. Observations showed that Bacopa's neuroprotective effects were comparable to those of l-deprenyl at both biochemical and microscopic levels.

Effects of high-dose selegiline on morphine reinforcement and precipitated withdrawal in dependent rats.

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects. Several lines of evidence suggest that treatment with selegiline at doses that exceed levels required for inhibition of MAO can produce distinct pharmacologic effects. The purpose of this study was to evaluate the effects of chronic treatment with high-dose selegiline on extinction responding, cue-induced reinstatement, morphine reinforcement and naloxone-precipitated withdrawal. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of 3.2 mg/kg per injection of morphine under a progressive ratio schedule. Daily treatment with saline or 6.4 mg/kg per day of selegiline was then administered over extinction, reinstatement and re-acquisition of morphine self-administration. To enhance or diminish the potential for psychostimulant effects, selegiline was administered either immediately prior to (pre-session) or 1 h following (post-session) extinction, reinstatement and self-administration sessions. Pre-session selegiline decreased the number of ratios completed on days 2, 3 and 4 of extinction, and decreased morphine self-administration during all four re-acquisition sessions. When administered at the same dose level, post-session selegiline decreased responding on the fourth extinction session, and was ineffective in modifying re-acquisition of self-administration. Selegiline administered by either schedule did not modify cue-induced reinstatement. Daily treatment with 6.4 mg/kg per day of selegiline did not modify self-administration of food under a progressive ratio schedule. Acute treatment with single, 6.4 mg/kg doses of selegiline attenuated naloxone-induced increases in ptosis and global withdrawal score, but did not modify any other sign of withdrawal or global withdrawal score calculated without ratings of ptosis. In conclusion, high-dose selegiline can attenuate extinction responding and morphine-reinforced behavior, and these effects may be mediated by psychostimulant metabolites.

Effects of repeated administration of Uncaria hooks on the acquisition and central neuronal activities in ethanol-treated mice.

The effects of the repeated administration of Uncaria hooks were examined on the impaired memory acquisition and the level of neurotransmitters in the cortex, hippocampus and striatum in ethanol-treated mice, in comparison with those with L-deprenyl and N-methyl-D-glucamine as positive controls. Ethanol-induced amnesia was significantly ameliorated by repeated administration of methanol extract and alkaloid fraction of Uncaria hooks, similar to in the positive controls. Treatment with methanol extract and alkaloid fraction of Uncaria hooks significantly reduced the ethanol-induced increase of dopamine in the hippocampus. The 5-hydroxytryptamine and glutamic acid neuronal activities were significantly changed by Uncaria hooks, but not by L-deprenyl, in all examined brain tissues of ethanol-treated mice. On the other hand, the GABAergic and cholinergic neuronal activities did not show any significant changes by Uncaria hooks in any of the examined brain tissues of the ethanol-treated animals. The results suggest that the extracts of Uncaria hooks exert a beneficial effect on ethanol-induced memory impairment, and that the central 5-hydroxytryptaminergic and glutaminergic neuronal systems play an important role in the memory acquisition of Uncaria hooks.

Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury.

We evaluated whether combined treatment with selegiline, a selective MAO-B inhibitor, and EGb 761, a standard extract of Ginkgo biloba, has synergistic effects against ischemic reperfusion injury (IRI) in gerbils. Interestingly, we observed that pretreatment with EGb 761 significantly attenuated selegiline-induced hyperactivity. This finding paralleled striatal fos-related antigen immunoreactivity (FRA-IR) in mice. Four minutes of bilateral carotid artery occlusion caused substantial cell loss in the CA1 of the hippocampus 5 days post-ischemic insult. Pretreatment with EGb 761, with or without selegiline, significantly attenuated this neuronal loss. Combined treatment with EGb 761 plus selegiline was more efficacious in preventing this loss. Synaptosomal formations of protein carbonyl, lipid peroxidation (malondialdehyde (MDA) + 4-hydroxyalkenal (4-HDA)), and reactive oxygen species (ROS) in the hippocampus remained elevated 5 days post-ischemic insult. The antioxidant effects appeared to be most significant in the group treated with EGb 761 plus selegiline. This combined treatment produced more significant attenuation of IRI-induced alterations in intramitochondrial calcium accumulation, the mitochondrial transmembrane potential, and mitochondrial Mn-superoxide dismutase-like immunoreactivity (Mn-SOD-IR) than either treatment alone. Our results suggest that co-administration of EGb 761 and selegiline produces significant neuroprotective effects via suppression of oxidative stress and mitochondrial dysfunction without affecting neurological function.