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It is fair to say that if I had not received a phone call at Oxford University from Prof. Merton Sandier in summer of 1973, that a young chap by the name of Peter Riederer, from Prof. Walter Birkmayer Department, was in London and wanted to discuss some aspects of monoamine oxidase (MAO) inhibitors for Parkinson’s disease (PD), I probably would not be where I am today. If there were two contrasting people, that were us. Here was this large but soft spoken, rather gentle and austere Viennese, meeting a small rather assertive individual from Iran. It was meeting of the minds and an instant connection that has lasted some 34 years, with a result of some near one hundred joint publications, some 25 books and hopefully advancing the prospect for treatment of PD. Peter wanted to know was there an MAO inhibitor that did not cause a “Cheese Reaction”, a side effect of first generation of non-selective MAO inhibitors, that could be employed in the treatment of PD. In 1961 Birkmayer and colleagues had used MAO inhibitors to treat PD, gastrointestinal and blood pressure problems in such patients was a limiting factor.

The nature of intracellular communication and integration in the central nervous system remained a source of controversy long after it had been accepted that the brain is intrinsically involved in the reception of external and internal sensory impressions, in the control of both voluntary and involuntary physiological functions, and in the processes associated with consciousness and psychic function in humans. The role of the specific chemistry of the brain in these functions was specifically addressed only in the 20th century, although chemical examination of brain tissue can be traced at least as far back as 1719 to Hensing’s Cerebri examen chemicum. Throughout the 1940s and 1950s evidence accumulated from a variety of laboratories that certain chemical substances, such as acetylcholine, noradrenaline and histamine, might be involved in central nervous system neurotransmission, but conclusive evidence for such communication was difficult to obtain. Commencing with Carlsson’s 1957 paper on the antireserpine effects of DOPA and culminating in the successful amelioration of parkinsonian akinesia by Birkmayer and Hornykiewicz via administration of L-DOPA in 1961, followed by the identification of specific nervous tracts which utilized dopamine as a transmitter, chemical neurotransmission in the brain was ultimately demonstrated through a combination of pharmacological, physiological and clinical research.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in industrialized countries. Present cell culture models for PD rely on either primary cells or immortal cell lines, neither of which allow for long-term experiments on a constant population, a crucial requisite for a realistic model of slowly progressing neurodegenerative diseases.

Isatin is an endogenous oxidized indole that influences a range of processes in vivo and in vitro. It has a distinct and discontinuous distribution in the brain and [^3H]isatin binding sites are widely distributed in rat brain sections. The highest labelling is found in hypothalamic nuclei and in the cortex, hippocampus, and cerebellum (Crumeyrolle-Arias et al., 2003). However, the properties of most isatin binding sites and their physiological ligands remain unknown. In the present study the effects of three endogenous oxidized indoles (oxindole, 5-hyxdoxyoxindole, and isatin) on [^3H]isatin binding were investigated in rat brain sections. In most regions cold isatin (0.2 mM) significantly reduced [^3H]isatin binding. In addition to isatin, the other endogenous oxidized indoles, 5-hydroxyoxindole and oxindole were effective in displacing [^3H]isatin.

The neuromelanin pigment of the substantia nigra of the human brain is closely associated with lipids and other non-melanogenic compounds which appear to contribute to the unique and complex morphology of neuromelanin pigment granules. In this work we show that insoluble granules isolated from the human substantia nigra associate in vitro to form pigment aggregates similar to those present in the human brain. Extraction of neuromelanin-associated polar lipids by methanol and/or hexane significantly enhanced melanin aggregate size. A marked (10-fold) increase in granule size was seen after methanol treatment, whereas the application of hexane after methanol reduced this pro-aggregation effect. We have previously reported that hexane and methanol remove the neuromelanin-associated polyisoprenoids dolichol and cholesterol respectively. Thus, the current data suggests that pigment-associated lipids may be a factor regulating pigment aggregation and neuromelanin granule size in vivo.

Hydrogen peroxide has been shown to act as a second messenger mediating intracellular redox-sensitive signal transduction. Here we show that hydrogen peroxide is also able to transmit pro-inflammatory signals from one cell to the other and that this action can be inhibited by extracellularly added catalase. If these data can be further substantiated, hydrogen peroxide might become as important as nitric oxide as a small molecule intercellular (first) messenger.

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntingtons disease (HD) and spinocerebellar ataxia (SCA1).

Catecholaminergic neurons of the primate substantia nigra (SN) pars compacta (SNc) and the locus coeruleus contain neuromelanin (NM) granules as characteristic structures underlying the pigmentation of these brain areas. Due to a phylogenetic appearance NM granules are absent in the rodent brain, but gradually become present in primates until they reach a maximal expression in humans. Although a possible mechanism of pigment formation may be autoxidation of the NM precursors dopamine or nor-adrenalin, several groups have suggested an enzymatic formation of NM mediated by tyrosinase or a related enzyme. Since tyrosinase mRNA is suggested to be expressed in the SN of mice and humans, we reinvestigated the expression of tyrosinase in the human SNc and the locus coeruleus at the protein level by immunohistochemistry and Western blot analysis, but could not detect tyrosinase in these brain regions.

Oxidative stress is central to neuronal damage in neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. In consequence, activation of the cerebral oxidative stress defence is considered as a promising strategy of therapeutic intervention. Here we demonstrate that the flavone luteolin confers neuroprotection against oxidative stress via activation of the nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor central to the maintenance of the cellular redox homeostasis. Luteolin protects rat neural PC12 and glial C6 cells from N-methyl-4-phenyl-pyridinium (MPP^+) induced toxicity in vitro and effectively activates Nrf2 as shown by ARE-reporter gene assays. This protection critically depends on the activation of Nrf2 since downregulation of Nrf2 by shRNA completely abrogates the protection of luteolin in vitro . Furthermore, the neuroprotective effect of luteolin is abolished by the inhibition of the luteolininduced ERK1 /2-activation. Our results highlight the relevance of Nrf2 for neural cell survival conferred by flavones. In particular, we identified luteolin as a promising lead for the search of orally available, blood brain barrier permeable compounds to support the therapy of neurodegenerative disorders.

The gaseous messenger nitric oxide (NO) has been implicated in a wide range of behaviors, including aggression, anxiety, depression, and cognitive functioning. To further elucidate the physiological role of NO and its down-stream mechanisms, we conducted behavioral and expressional phenotyping of mice lacking the neuronal isoform of nitric oxide synthase (NOS-I), the major source of NO in the central nervous system. No differences were observed in activity-related parameters; in contrast to the a priori hypothesis, derived from pharmacological treatments, depression-related tests (Forced Swim Test, Learned Helplessness) also yielded no significantly different results. A subtle anxiolytic phenotype however was present, with knockdown mice displaying a higher open arm time as compared to their respective wildtypes, yet all other investigated anxiety-related parameters were unchanged. The most prominent feature however was gender-independent cognitive impairment in spatial learning and memory, as assessed by the Water Maze test and an automatized holeboard paradigm. No significant dysregulation of monoamine transporters was evidenced by qRT PCR. To further examine the underlying molecular mechanisms, the transcriptome of knockdown animals was thus examined in the hippocampus, striatum and cerebellum by microarray analysis. A set of > 120 differentially expressed genes was identified, whereat the hippocampus and the striatum showed similar expressional profiles as compared to the cerebellum in hierarchical clustering.