Effect Of Deprenyl Research Articles

The effect of a neuroprotective dose of isatin or deprenyl to mice on the profile of brain isatin-binding proteins

Isatin (indol-2,3-dione), an endogenous biofactor found in the brain, peripheral tissues and biological body fluids of humans and animals, exhibits a wide range of biological and pharmacological activities. They are realized via interaction with numerous isatin-binding proteins. Some of these proteins identified during proteomic profiling of the brain are involved in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl (selegiline), a pharmacological agent used for treatment of Parkinson's disease. In this study, we have investigated the effect of a single dose administration of isatin (100 mg/kg) and deprenyl (10 mg/kg) to mice on the profile of the brain isatin-binding proteins. Comparative proteomic analysis of brain isatin-binding proteins of mice treated with isatin or deprenyl resulted in identification of a representative group of proteins (n=200) sensitive to the administration of these substances. The change in the profile of isatin-binding proteins may be obviously attributed to accumulation of isatin and deprenyl in the brain and their interaction with target proteins; this prevents protein binding to the affinity sorbent. Thus identified brain isatin-binding proteins of the control animals obviously represent specific targets that interact directly with isatin (and also with deprenyl) in vivo. Isatin or deprenyl administered to animals interact with these proteins and thus inhibit their binding to the affinity sorbent (immobilized isatin analogue).

The Effect of Deprenyl and Isatin Administration to Mice on the Proteomic Profile of Liver Isatin-Binding Proteins

The Effect of Deprenyl and Isatin Administration to Mice on the Proteomic Profile of Liver Isatin-Binding Proteins

The effect of deprenyl and isatin administration to mice on the proteomic profile of liver isatin-binding proteins

Isatin (indol-2,3-dione) is an endogenous indole found in the brain, peripheral tissues and biological body fluids of humans and animals. Its wide spectrum of biological activity is realized via interaction with numerous isatin-binding proteins; these include proteins playing an important role in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl, a pharmacological agent used for treatment of Parkinson's disease. In this study, the effects of the course of deprenyl (1 mg/kg) and isatin (20 mg/kg) administration for 21 days on the profile of the isatin-binding proteins of the liver of mice have been investigated. Proteomic profiling of liver isatin-binding proteins of control mice by means of 5-aminocaproylisatin as an affinity ligand resulted in identification of 105 proteins. Treatment of animals with a low dose of isatin slightly decreased (up to 91), while injections of deprenyl slightly increased (up to 120) the total number of isatin-binding proteins. 75 proteins were common for all three groups; they represented from 62.5% (in deprenyl treated mice) and 71% (in control mice), to 82% (isatin treated mice) of the total number of identified liver isatin-binding proteins. Proteomic analysis of the isatin-binding proteins of mice treated with isatin (20 mg/kg) or deprenyl (1 mg/kg) for 21 days revealed a representative group of proteins (n=30) that were sensitive to the administration of these substances. Taking into account the previously obtained results, it is reasonable to suggest that the change in the profile of isatin-binding proteins may be attributed to accumulation of isatin and deprenyl in the liver and interaction with target proteins prevents their subsequent binding to the affinity sorbent. In this context, the identified isatin-binding liver proteins of control animals that do not bind to the affinity sorbent (immobilized isatin analogue) after treatment of animals with either deprenyl or isatin appear to be specific targets directly interacting with isatin in vivo.

DYNAMIC PREDICTION FOR MULTIPLE REPEATED MEASURES AND EVENT TIME DATA: AN APPLICATION TO PARKINSON'S DISEASE.

In many clinical trials studying neurodegenerative diseases such as Parkinson's disease (PD), multiple longitudinal outcomes are collected to fully explore the multidimensional impairment caused by this disease. If the outcomes deteriorate rapidly, patients may reach a level of functional disability sufficient to initiate levodopa therapy for ameliorating disease symptoms. An accurate prediction of the time to functional disability is helpful for clinicians to monitor patients' disease progression and make informative medical decisions. In this article, we first propose a joint model that consists of a semiparametric multilevel latent trait model (MLLTM) for the multiple longitudinal outcomes, and a survival model for event time. The two submodels are linked together by an underlying latent variable. We develop a Bayesian approach for parameter estimation and a dynamic prediction framework for predicting target patients' future outcome trajectories and risk of a survival event, based on their multivariate longitudinal measurements. Our proposed model is evaluated by simulation studies and is applied to the DATATOP study, a motivating clinical trial assessing the effect of deprenyl among patients with early PD.

Robust Bayesian hierarchical model using normal/independent distributions.

The multilevel item response theory (MLIRT) models have been increasingly used in longitudinal clinical studies that collect multiple outcomes. The MLIRT models account for all the information from multiple longitudinal outcomes of mixed types (e.g., continuous, binary, and ordinal) and can provide valid inference for the overall treatment effects. However, the continuous outcomes and the random effects in the MLIRT models are often assumed to be normally distributed. The normality assumption can sometimes be unrealistic and thus may produce misleading results. The normal/independent (NI) distributions have been increasingly used to handle the outlier and heavy tail problems in order to produce robust inference. In this article, we developed a Bayesian approach that implemented the NI distributions on both continuous outcomes and random effects in the MLIRT models and discussed different strategies of implementing the NI distributions. Extensive simulation studies were conducted to demonstrate the advantage of our proposed models, which provided parameter estimates with smaller bias and more reasonable coverage probabilities. Our proposed models were applied to a motivating Parkinson's disease study, the DATATOP study, to investigate the effect of deprenyl in slowing down the disease progression.

Restorative role of Deprenyl on Mitochondrial function of aging rat cerebellum

Mitochondria are known to be a rich source for the production of free radicals and, consequently, mitochondrial components are susceptible to lipid peroxidation that decreases respiratory activity. The present investigation was designed to evaluate the neuroprotective effect of Deprenyl on mitochondrial function in rats with respect to changes in the mitochondrial energy status. Intraperitoneal administration of liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p, significantly P< 0.05) to the experimental rats of three age groups (6, 12 &18 months old) prevented the age related reduction in Tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase and malate dehydrogenase) and respiratory marker enzymes (NADH dehydrogenase and cytochrome-c-oxidase) in the cerebellar mitochondria. The results of the present study indicate that the overall neuroprotective effect of deprenyl is probably related to its ability to retain the energy status of cerebellum by preserving the activities of Tricarboxylic acid cycle enzymes and respiratory marker enzymes at near normalcy and/or to its free radical- scavenging capability against age related aberrations in lipid peroxidation, which is responsible for unalterable changes in neuronal membrane.

Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by L-Deprenyl

Background: Development of mammary tumors is an age-associated phenomenon that is likely due to deficits in the neuroendocrine-immune interactions. Previously, we demonstrated that <smlcap>L</smlcap>-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, can enhance immune responses and restore noradrenergic (NA) innervation in the spleens of rats with carcinogen-induced and spontaneously developing mammary tumors. Objectives: To investigate whether (1) treatment of early middle-aged female rats would prevent the spontaneous development of mammary tumors accompanied by restoration of immunity in the spleen and draining lymph nodes (DLN) and sympathetic NA innervation in the spleen and (2) deprenyl can influence the proliferation of estrogen receptor (ER)-positive (MCF-7 and T47D) and ER-negative (MDA-MB-231 and Hs 578T) human breast cancer cells. Methods: Early middle-aged (8- to 9-month-old) female Sprague-Dawley rats were treated with 0, 1.0 or 2.5 mg of deprenyl/kg body weight (BW) daily i.p. for 12 months. Cells of ER-positive (ER+) and ER-negative (ER-) human breast cancer cell lines were incubated with media or 10^-3 to 10^-8<smlcap>M</smlcap> deprenyl for 1, 2, 4 or 6 days to examine the proliferation of cells. Results: Tumor incidence increased in saline-treated old female rats, while deprenyl treatment significantly reduced the incidence of mammary tumors in these rats. Saline-treated tumor-bearing rats exhibited reduced splenic NA innervation and norepinephrine (NE) content, splenic interleukin (IL)-2 and interferon (IFN)-γ levels and NK cell activity as well as DLN IL-2 and IFN-γ levels compared to young female rats without tumors. In contrast, treatment with 2.5 mg/kg of deprenyl enhanced IL-2 and IFN-γ production in both the spleen and DLN as well as splenic natural killer (NK) cell activity. Deprenyl treatment also increased concanavalin A (Con A)-induced proliferation of T lymphocytes in the DLN. Deprenyl-induced changes in immune responses were accompanied by enhanced NA innervation and NE content in the spleen. In vitro incubation of various concentrations of deprenyl with ER+ human breast cancer cell lines partly inhibited the proliferation of cells, while it had no effect on the ER- breast cancer cells. Conclusions: These results suggest that (1) development of mammary tumors is mediated through the loss of immunity and sympathetic NA nerve fibers accompanied by reduced NE levels in the spleen, (2) the prevention of mammary tumor development by deprenyl may involve the reversal of the tumor-associated decline in sympathetic NA activity and cell-mediated immune responses in the spleen and DLN and (3) the antitumor effects of deprenyl may be partially mediated through ER-dependent intracellular signaling pathways.

L-Deprenyl Reverses Age-Associated Decline in Splenic Norepinephrine, Interleukin-2 and Interferon-γ Production in Old Female F344 Rats

Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced natural killer cell activity, interleukin (IL)-2 and interferon (IFN)-γ production, and T- and B-cell proliferation, suggesting possible links between sympathetic activity and immunosenescence. Objectives: The aim of this study is to investigate the effects of <smlcap>l</smlcap>-(–)-deprenyl, a monoamine oxidase-B inhibitor, on the sympathetic nervous system and cell-mediated immune responses in old female rats. Methods: Low doses of <smlcap>l</smlcap>-deprenyl (0.25 or 1.0 mg/kg body weight, BW) were administered intraperitoneally to 19- to 21-month-old female F344 rats for 8 weeks. To assess the stereoselectivity of the effects of deprenyl on splenic sympathetic activity and immune responses, the <smlcap>d</smlcap>-enantiomer (<smlcap>d</smlcap>-(+)-deprenyl; 1.0 mg/kg BW) was also included in the studies. Norepinephrine (NE) concentration and content, and mitogen-induced T-cell proliferation and cytokine production were assessed in the splenocytes after deprenyl treatment. Results: Treatment with <smlcap>l</smlcap>-deprenyl reversed the age-related decrease in NE concentration and content and IFN-γ production, and increased IL-2 production in the spleen while <smlcap>d</smlcap>-deprenyl did not affect the age-associated reduction in splenic NE levels or cytokine production. Conclusions: These findings demonstrate that <smlcap>l</smlcap>-deprenyl exerts neurorestorative and immunostimulatory effects on the sympathetic nervous system and cell-mediated immune responses during aging and provides evidence for a causal relationship between some aspects of immunosenescence and the age-related decline in sympathetic nerves in the spleens of female F344 rats.

Effect of MAO-B Inhibition against Ischemia-induced Oxidative Stress in the Rat Brain

An increasing number of reports suggest the involvement of oxidative stress in neurodegenerative diseases where the increased formation of reactive oxygen species (ROS) leads to neuronal damage and cell death. Dopamine may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia/reperfusion-induced damage. Monoamine oxidase (MAO) enzyme (particularly MAO-B) is responsible for metabolizing dopamine and plays an important role in oxidative stress through altering the redox state of neuronal and glial cells. MAO participates in the generation of hydroxyl radicals during ischemia/reperfusion. This suggests the possible use of MAO inhibitors as neuroprotective agents for treating ischemic injury. The protective effect of deprenyl (N-methyl-N-(1-methyl-2-phenyl-ethyl)-prop-2-yn-1-amine, CAS 14611-51-9) (2 and 10 mg/kg), a MAO-B inhibitor, and beta-carotene (10 and 20 mg/kg), a natural antioxidant, was examined in a rat model of cerebral ischemia. Ischemia was induced in rats by bilateral carotid artery occlusion for 1 h followed by declamping for another hour. The effect of the drugs on the brain activity of lactate dehydrogenase (LDH) and some of the oxidative stress biomarkers such as brain activity of superoxide dismutase (SOD) and catalase (CAT) enzymes and brain malondialdehyde (MDA) content was determined. In addition, the content of catecholamines such as noradrenaline (NA) and dopamine (DA) was determined. Deprenyl decreased the ischemia-induced elevation of LDH activity and MDA content and normalized the SOD activity. In addition, deprenyl increased the CAT activity back to normal, and increased the noradrenaline and dopamine content in the brain of rats. Beta-carotene administration ameliorated the effect of ischemia followed by reperfusion (I/R) demonstrated as decreasing the LDH activity and MDA content and by increasing the SOD activity. The drug also increased CAT activity in the brain of rats. However, beta-carotene did not alter the NA and DA content. These results indicate that deprenyl protected the rat brains against the ischemia-induced oxidative damage, an effect which might be explained through multiple mechanisms, possibly due to reduction of dopamine catabolism with a subsequent increased activity on dopaminergic D2 receptors and suppressing the action of ROS as well.

Deprenyl increases synaptophysin and choline acetyltransferase in rat after sciatic nerve axotomy

Neuroprotective effect of deprenyl on motoneurons of spinal cord after axotomy of peripheral nerves such as sciatic has been well established. Deprenyl is an inhibitor of monoamine oxidase type-B (MAO-B). The main function of this agent is the release of neurotransmitters from pre-synaptic terminals. Acetylcholine is a neurotransmitter that is synthesized by choline acetyltransferase (ChAT) and is widely used as a marker to assess the function of neurons. Synaptophysin is one of the synaptic vesicle neuronal terminal residual proteins which is also used as a marker for some neurotransmitters.The aim of this research was to study the effect of deprenyl (2.5 mg/kg) injection on synaptophysin and ChAT immunoreactivity. The intraperitoneal injection of deprenyl was done following axotomy and continued for 21 days. Then, the animals were perfused with paraformaldehyde (4%) and spinal cord segment L4-L6 proccessed for immunohistochemistry. The results obtained in this study showed that deprenyl-treated axotomized mice had higher ChAT and synaptophysin expression as compared to untreated axotomized animals.

Age-related protective effect of deprenyl on changes in the levels of diagnostic marker enzymes and antioxidant defense enzymes activities in cerebellar tissue in Wistar rats

Antioxidants are free radical scavengers and protect living organisms against oxidative damage to tissues. Experimental evidence implicates oxygen-derived free radicals as important causative agents of aging and the present study was designed to evaluate the age-related effects of deprenyl on the antioxidant defense in the cerebellum of male Wistar rats. Experimental rats of three age groups (6, 12, and 18 months old) were administered with liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p) and levels of diagnostic marker enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase) in plasma, lipid peroxides, reduced glutathione and activities of glutathione-dependent antioxidant enzymes (glutathione peroxidase and glutathione-S-transferase) and antiperoxidative enzymes (catalase and superoxide dismutase) in the cerebellar tissue were determined. Intraperitonial administration of deprenyl (2 mg/kg body weight/day for a period of 15 days) significantly (p < 0.05) attenuated the age-related alterations noted in the levels of diagnostic marker enzymes plasma of experimental animals. Deprenyl also exerted an antioxidant effect against aging process by hindering lipid peroxidation to an extent. Moderate rise in the levels of reduced glutathione and activities of glutathione-dependent antioxidant enzymes and antiperoxidative enzymes was also observed. The results of the present investigation indicated that the protective potential of deprenyl was probably due to the increase of the activity of the free radical scavenging enzymes or to a counteraction of free radicals by its antioxidant nature or to a strengthening of neuronal membrane by its membrane-stabilizing action. Histopathological observations also confirmed the protective effect of deprenyl against the age-related aberrations in rat cerebellum. These data on the effect of deprenyl on parameters of normal aging provides new additional information concerning the anti-aging potential of deprenyl.

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.

Effect of Deprenyl on Free Radical Oxidation in Rat Brain during Immobilization Stress

Rarely repeated episodes of 1-h immobilization in rats were accompanied by an increase in the content of molecular products of lipid peroxidation and decrease in the amount of oxidatively modified proteins. Monoamine oxidase B inhibitor deprenyl prevented the poststress activation of lipid peroxidation.

Deprenyl and its metabolites in neuroprotection

Background and aims: The dose dependent pro and anti apoptotic feature of deprenyl treatment has been documented. One possible mechanism behind these effects can be the up-regulation of Bcl-2 protein, as we have published previously (Simon et al., 2002). In PC12 cell culture we demonstrated that the cytoprotective effect of deprenyl is related to the stabilization of mitochondrial membrane and the decrease of reactive oxygen species (ROS). Furthermore the drug decreased significantly the TUNEL labeled and TUNEL-caspase-3 double labeled neurons in the penumbra region after permanent MCA occlusion in rats. In the present study we investigated the cytoprotective effect of a deprenyl metabolite, deprenyl-N-oxid (DNO), which is the most recently synthesized metabolite of deprenyl.

Antioxidant and antiapoptotic activities of deprenyl and estradiol co-administration in aged rat kidney

Aging is a progressive degeneration process in living organisms. Deprenyl is an irreversible monoamine-oxidase B inhibitor which has antioxidant, antiapoptotic and neuroprotective effects. Estradiol is also a neuroprotective and antioxidant hormone. The objective of this study was to determine whether the antioxidative effects of deprenyl can suppress apoptotic activity, with or without estradiol, in aged female rat kidney. Wistar Albino female rats were divided into six groups as follows; young (3 months old) control, aged (24 months old) control, aged deprenyl treated, aged estradiol treated, aged deprenyl plus estradiol treated and sham. All rats except for the sham group were injected for 21 days. Determination of oxidative stress parameter was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining and caspase-3 immunohistochemistry were performed. Deprenyl and estradiol administration, alone or in combination, decreased significantly the levels of lipid peroxidation relative to aged control and sham-injected rats. The number of TUNEL positive cells decreased significantly in deprenyl and estradiol-treated rats compared with aged control and sham rats. Deprenyl and estradiol replacement attenuated age-related changes in renal morphology. The results indicate that deprenyl treatment alone, or in combination with estradiol, may modulate age-related apoptotic changes in rat kidney by decreasing oxidative stress.

Suppression of apoptosis and oxidative stress by deprenyl and estradiol in aged rat liver

Aging is accompanied by significant structural and functional transformations of all organs and systems. Age-associated increase in apoptotic behavior may cause disease. Older cells are more susceptible to endogenous oxidative damage, and oxidative stress is a potent inducer of apoptosis. Deprenyl is an irreversible monoamine-oxidase B inhibitor which has anti-oxidant, anti-apoptotic and neuroprotective effects. Estrogen is also a neuroprotective and anti-oxidant hormone. The objectives of this study were to determine whether the anti-oxidative effects of deprenyl can suppress apoptotic activity, with or without estradiol, in aged female rat livers. In this study, ovariectomized female Wistar albino rats were divided into six groups as follows; young (3 months old) saline-treated control, aged (24 months old) saline-treated control, aged deprenyl treated, aged estradiol treated, aged deprenyl plus estradiol treated and aged sham controls. All rats except for the sham group were treated for 21 days. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining was performed. The results were analyzed by one-way ANOVA post hoc Bonferroni test. Deprenyl and estradiol administration, alone or in combination, decreased significantly the levels of lipid peroxidation and increased superoxide dismutase activity in the liver relative to aged control and sham rats (P<0.05). The number of TUNEL positive cells decreased significantly in deprenyl and estradiol-treated rats compared with aged control and sham rats. The results indicate that deprenyl treatment alone, or in combination with estradiol, may modulate age-related apoptotic changes in rat liver by decreasing oxidative stress.

Improvement of mouse brain mitochondrial function after deprenyl treatment

Deprenyl is a selective monoamine oxidase (MAO) B inhibitor, widely used for treatment of Parkinson’s disease. The present study shows that deprenyl treatment was able to improve mitochondrial function. Fourteen month old mice were injected i.p. with deprenyl (20 mg/kg) and killed 1.5 h after the administration. Different brain subcellular fractions were isolated from control and deprenyl-treated animals to evaluate the effect of deprenyl on nitric oxide synthase (NOS) activity. Oxygen consumption, hydrogen peroxide (H2O2) production, mitochondrial membrane potential and calcium-induced permeability transition (MPT) were studied in intact mitochondria. In addition, the effect of deprenyl on respiratory complexes and MAO activities were evaluated in submitochondrial particles (SMP).Monoamine oxidase activity was found to be decreased by 55% in mitochondria from deprenyl-treated animals and as a consequence, H2O2 production was significantly decreased. Deprenyl inhibited NOS activity in cytosolic fractions and SMP by 40% and 55%, respectively. In similar conditions, SMP from deprenyl-treated animals showed increased cytochrome oxidase activity. A 51% increase in the oxygen uptake in state 3 (active respiration state) was found after deprenyl treatment, but no significant changes were observed in state 4 (resting respiration state). Deprenyl treatment protected against calcium-induced depolarization and was able to inhibit calcium-induced MPT.This work provides evidence that deprenyl treatment exerts an improvement of brain mitochondrial function, through a reduction of free radical production, prevention of calcium-induced MPT and maintaining a mitochondrial transmembrane potential.

Mitogen activated protein kinase and protein kinase C activation mediate promotion of sAPPα secretion by deprenyl

The beta amyloid cascade plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Therefore, drugs that regulate amyloid precursor protein (APP) processing toward the nonamyloidgenic pathway may have therapeutic potential. Many anti-dementia drugs can regulate APP processing in addition to their pharmacological properties. Deprenyl is a neuroprotective agent used to treat some neurodegenerative diseases, including AD. In the present study, the effects of deprenyl on APP processing were investigated. Using SK-N-SH and PC12 cells, it was demonstrated that deprenyl stimulated the release of the nonamyloidogenic α-secretase form of soluble APP (sAPPα) in a dose-dependent manner without affecting cellular APP expression. The increase of sAPPα secretion by deprenyl was blocked by the mitogen activated protein (MAP) kinase inhibitor U0126 and PD98059, and by the protein kinase C (PKC) inhibitor GF109203X and staurosporine, suggesting the involvement of these signal transduction pathways. Deprenyl induced phosphorylation of p42/44 MAP kinase, which was abolished by specific inhibitors of MAP kinase and PKC. Deprenyl also phosphorylated PKC and its major substrate, and myristoylated alanine-rich C kinase (MARCKS) at specific amino acid residues. The data also indicated that 10 μM deprenyl successfully induced two PKC isoforms involved in the pathogenesis of AD, PKCα and PKCɛ, to translocate from the cytosolic to the membrane fraction. This phenomenon was substantiated by immunocytochemistry staining. These data suggest a novel pharmacological mechanism in which deprenyl regulates the processing of APP via activation of the MAP kinase and PKC pathways, and that this mechanism may underlie the clinical efficacy of the drug in some AD patients.

Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats

Oxidative stress may play a major role in the aging process and associated cognitive decline. Therefore, antioxidant treatment may alleviate age-related impairment in spatial memory. Cognitive impairment could also involve the age-related morphological alterations of the hippocampal formation. The aim of this study was to examine the relationship between the effects of deprenyl, an irreversible monoamine-oxidase B inhibitor, on spatial memory by oxidant stress and on the total number of neurons in the hippocampus CA1 region of aged male rats. In this study, 24-month-old male rats were used. Rats were divided into control and experimental groups which received an injection of deprenyl for 21 days. Learning experiments were performed for six days in the Morris water maze. Spatial learning was significantly better in deprenyl-treated rats compared to saline-treated rats. Deprenyl treatment elicited a significant decrease of lipid peroxidation in the prefrontal cortex, striatum and hippocampus regions and a significant increase of glutathione peroxidase activity in the prefrontal cortex and hippocampus. It was observed that deprenyl had no effect on superoxide dismutase activity. The total number of neurons in the hippocampus CA1 region was significantly higher in the deprenyl group than in the control group. In conclusion, we demonstrated that deprenyl increases spatial memory performance in aged male rats and this increase may be related to suppression of lipid peroxidation and alleviation of the age-related decrease of the number of neurons in the hippocampus. The results of such studies may be useful in pharmacological alleviation of the aging process.

Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins

Neuroprotection has received considerable attention as a strategy for the treatment of Parkinson’s disease (PD). Deprenyl (Selegiline) is a promising candidate for neuroprotection; however, its cytoprotective mechanism has not been fully clarified. Here, we report a novel cytoprotective mechanism of deprenyl involving PI3K and Nrf2-mediated induction of oxidative stress-related proteins. Deprenyl increased the expression of HO-1, PrxI, TrxI, TrxRxI, γGCS, and p62/A170 in SH-SY5Y cells. Deprenyl also induced the nuclear accumulation of Nrf2 and increased the binding activity of Nrf2 to the enhancer region of human genomic HO-1. The Nrf2-mediated induction of antioxidative molecules was controlled by PI3K. Indeed, furthermore, neurotrophin receptor TrkB was identified as an upstream signal for PI3K–Nrf2 activation by deprenyl. These results suggest that the cytoprotective effect of deprenyl is, in part, dependent on Nrf2-mediated induction of antioxidative proteins, suggesting that activation of the PI3K–Nrf2 system may be a useful therapeutic strategy for PD.