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Nigrostriatal neurodegeneration in Parkinson’s disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 μg/side), into the medial forebrain bundle. Administration of rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only rasagiline managed to restore the nigrostriatal degeneration. Furthermore, rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD. [ABSTRACT FROM AUTHOR]

Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer's disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression. [ABSTRACT FROM AUTHOR]

Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-β protein (Aβ) in reducing iron-induced neurotoxicity. Thus, given that A? possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Aβ, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Aβ levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD. [ABSTRACT FROM AUTHOR]

Dysfunction of the ubiquitin-proteasome system (UPS) and accumulation of iron in substantia nigra (SN) are implicated in the pathogenesis of Parkinson's disease (PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine (DA) neurons. In the present study, we use a new brain-permeable iron chelator, VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline], and its derivative M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor (lactacystin) -induced nigrostriatal degeneration. Bilateral microinjections of lactacystin (1.25 µg/side) into the mouse medial forebrain bundle were performed. Administration of VK-28 (5 mg/kg, once a day) or M30 (5 mg/kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK-28 and M30 both significantly improved behavioral performances and attenuated lactacystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain-permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK-28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD. [ABSTRACT FROM AUTHOR]

Activin is a member of the transforming growth factor-β superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin βA or βB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration. [ABSTRACT FROM AUTHOR]

The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-( R)-aminoindan. In the current study, the neuroprotective properties of 1-( R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1–1 μmol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindan-induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCε. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [( N-propargyl-(3 R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a severe neurodegenerative disorder, with no drugs currently approved to prevent the neuronal cell loss characteristic of brains of patients suffering from PD. Owing to the complex etiology of PD, an innovative approach towards neuroprotection or neurorescue may be the use of multifunctional pharmaceuticals that target an array of pathological pathways, each of which is believed to contribute to the cascade that ultimately leads to neuronal cell death. In this review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorescue therapeutics in PD. The compounds discussed originate from synthetic chemistry as well as from natural sources. [ABSTRACT FROM AUTHOR]

Evaluation of: Liu G, Men P, Harris PL et al.: Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci. Lett. 406, 189-193 (2006). Current therapies for Alzheimer's disease (AD) are, at best, symptomatic. Cholinesterase inhibitors and memantine are intended for the treatment of cognitive symptoms, but offer only partial benefit without any disease-modifying activity. The involvement of iron in AD includes its deposition in the affected areas, the ability to promote oxidative stress and amyloid β-peptide aggregation and formation as a consequence of iron-dependent translation of amyloid precursor protein mRNA via the amyloid precursor protein 5'untranslated region. These findings have led to a new therapeutic approach for AD, involving iron-chelating compounds with limited neurotoxicity and, more recently, their encapsulation in the form of nanoparticles to facilitate blood-brain-barrier penetration. [ABSTRACT FROM AUTHOR]

The aim of the present study was to gain a deeper insight into the cell signaling pathways involved in the neuroprotection/neurorescue activity of the major green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG). EGCG (1 μm) caused an immediate (30 min) down-regulation (∼40%) of Bad protein levels, and a more pronounced reduction after 24 h (55%) in the human neuroblastoma cell line SH-SY5Y. Co-treatment with EGCG and the protein synthesis inhibitor cycloheximide prominently shortened Bad half-life, with as little as 30% of the Bad protein content remaining after 2 h, suggesting an effect of EGCG on Bad protein degradation. Accordingly, the proteasome inhibitors MG-132 and lactacystin damped Bad down-regulation by EGCG. The general protein kinase C (PKC) inhibitor GF109203X, or the down-regulation of conventional and novel PKC isoforms, abolished EGCG-induced Bad decline. However, no inhibition was seen with the cell-permeable myristoylated pseudosubstrate inhibitor of the atypical PKCζ isoform. The enforced expression of Bad for up to 72 h rendered the cells more susceptible to serum deprivation-induced cell death, whereas EGCG treatment significantly improved cell viability (up to 1.6-fold). The present study reveals a novel pathway in the neuroprotective mechanism of the action of EGCG, which involves a rapid PKC-mediated degradation of Bad by the proteasome. [ABSTRACT FROM AUTHOR]

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple CNS targets. We have synthesized a multifunctional non-toxic, brain permeable iron chelator drug, M-30, possessing propargyl monoamine oxidase (MAO) inhibitory neuroprotective and iron-chelating moieties, from our prototype iron chelator VK-28. In the present study M-30 was shown to possess a wide range of pharmacological activities, including pro-survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and β-amyloid (Aβ) levels. M-30 was found to decrease apoptosis of SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via reduction of the pro-apoptotic proteins Bad and Bax, and inhibition of the apoptosis-associated phosphorylated H2A.X protein (Ser 139) and caspase 3 activation. In addition, M-30 induced the outgrowth of neurites, triggered cell cycle arrest in G0/G1 phase and enhanced the expression of growth associated protein-43. Furthermore, M-30 markedly reduced the levels of cellular APP and β-C-terminal fragment (β-CTF) and the levels of the amyloidogenic Aβ peptide in the medium of SH-SY5Y cells and Chinese hamster ovary cells stably transfected with the APP ‘Swedish’ mutation. Levels of the non-amyloidogenic soluble APPα and α-CTF in the medium and cell lysate respectively were coordinately increased. These properties, together with its brain selective MAO inhibitory and propargylamine- dependent neuroprotective effects, suggest that M-30 might serve as an ideal drug for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, in which oxidative stress and iron dysregulation have been implicated. [ABSTRACT FROM AUTHOR]

The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that ‘silver bullet’ agents are superior to ‘dirty drugs’ in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of several multifunction drugs. These include ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], which combines the pharmacophore-neuroprotective effects of rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine or iron chelating moiety such as M30. In the case of M30 the pharmacophore of brain permeable iron chelator VK-28 plus the MAO inhibitor-neuroprotective propargylamine moiety of rasagiline are combined in a single molecule as a potential treatment for Alzheimer's disease, Lewy body disease, and Parkinson's disease with dementia. Here, we discuss the activities of ladostigil in terms of its cholinesterase cognitive enhancing potential, antiParkinson, antidepressant, neuroprotection and APP (amyloid precursor protein) processing potential. One major attribute of ladostigil is its neuroprotective activity in neuronal cell cultures and in vivo. Employing an apoptotic model of neuroblastoma SK-N-SH cells, the molecular mechanism of its neuroprotective activity has been determined. The current studies show that ladostigil significantly decreased apoptosis via inhibition of the cleavage and prevention of caspase-3 activation through a mechanism related to regulation of the Bcl-2 family proteins, resulting in reduced levels of Bad and Bax and induced levels of Bcl-2. In addition, ladostigil elevated the levels of pPKC(pan). We have also followed the regulation of APP processing and found that ladostigil markedly decreased apoptoticinduced levels of holo-APP, as well as stimulated the release of the non-amyloidogenic soluble APP (sAPPα) into the conditioned medium via a established protein kinsae C-MAPkinase dependent pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor lacking MAO inhibitory activity, exerted similar neuroprotective properties and APP processing, suggesting that the mode of action is independent of MAO inhibition. These effects were shown to reside in the propargylamine moiety. These findings indicate that the dual actions of the anti-apoptotic-neuroprotective activity and the ability to modulate APP processing, could make ladostigil a potentially valuable drug for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.British Journal of Pharmacology (2006) 147, S287–S296. doi:10.1038/sj.bjp.0706464 [ABSTRACT FROM AUTHOR]

The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats.Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%.Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels.In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg−1) or L-tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior.Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).British Journal of Pharmacology (2005) 146, 553–560. doi:10.1038/sj.bjp.0706355; published online 8 August 2005 [ABSTRACT FROM AUTHOR]

Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO-B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO-B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO-B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain homogenates with IC50 values (12–16 µ m), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 µ m were able to attenuate cell death induced by serum deprivation and by 6-hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti-Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent non-selective MAO-A and MAO-B inhibitor (IC50 < 0.1 µ m). However, HLA20 was more selective for MAO-B but had poor MAO inhibition, with an IC50 value of 64.2 µ m. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 ± 0.02; MAO-B, 0.057 ± 0.01). Acute (1–5 mg/kg) and chronic [5–10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days] in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP ( N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine. [ABSTRACT FROM AUTHOR]

Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin-proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin-proteasome subunits), dopaminergic transmission! metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased ex- pressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development. [ABSTRACT FROM AUTHOR]

Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl- (1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N- propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKC&3x03B5; mRNA; induction of Bcl-XL, Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCγ, Bad, and Bax mRNAs. More- over, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagilne. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, δψm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of δψm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced δψm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyll(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the/t@m reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Salinduced loss of δψm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline. [ABSTRACT FROM AUTHOR]

In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D[sub 1]-D[sub 2] receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity. However, only R-APO prevented nigro-striatal neuronal cell degeneration, as indicated by the immunohistochemistry of TH positive neurones in substantia nigra and by western analysis of striatal TH content. R-APO prevented the reduction of striataI-GSH and the increase in the ratio of GSSG over total glutathione, caused by MPTP treatment. In vitro both R-APO and S-APO inhibited monoamine oxidase A and B activity at relatively high concentrations (100 and 300 μmol/L, respectively). The elevated activity of TH induced by the two enantiomers may contribute to the maintenance of normal DA levels, suggesting that one of the targets of these molecules may involve upregulation of TH activity. It is suggested that the antioxidant and iron-chelating properties, possible monoamine oxidase inhibitory actions, together with activation of DA receptors, may participate in the mechanism of neuroprotection by APO enantiomers against MPTP. [ABSTRACT FROM AUTHOR]

Investigates the effects of rasagiline and its S-optical isomer TVP1022 on the regulation of amyloid precursor protein (APP) processing and the signaling pathways involved. Pretreatment of PC12 cells with the zinc metalloproteinase Ro31-9790; Activation of mitogen-activated protein kinase (MAPK) by rasagiline; Importance of the propargylamine moiety in rasagiline and its derivatives in MAPK dependent APP processing.