The effect of low oral doses of (?)-deprenyl and its metabolites on DSP-4 toxicity

Haberle, D.; Szökő, Éva; Halász, A; Magyar, K.

doi:10.1007/s007020100002

Cited by 7 publications

(3 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unknown if DSP4 has similar effects in mice. The loss of tissue NE content in forebrain regions like the cortex and HP appears to be more pronounced and persistent in mice than in rats (Haberle et al, 2001; Archer and Fredriksson, 2006; Dailly et al, 2006; Thomas et al, 2007). A loss of noradrenergic LC neurons has been documented following DSP4 in mice but the treatment involved two 50 mg/kg doses (Heneka et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

et al. 2010

View full text Add to dashboard Cite

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days, 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha1-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α2-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a LOSS of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.

show abstract

Section: Discussionmentioning

confidence: 95%

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Neuroprotective and neuronal rescue effects of R-(2)-deprenyl, unrelated to MAO-B inhibition but also highly stereoselective, have also been reported [20][21][22][23][24][25]. The protective effect of selegiline against DSP-4 toxicity [24], as well as its anti-apoptotic effect on serum-deprived cultured cells [25] could be abolished by pretreatment with SKF-525-A, a competitive inhibitor of drug metabolizing enzymes, indicating that a metabolite or some metabolites rather than the parent compound is (are) responsible for these pharmacological effects. However, the dealkylated me- tabolites do not inhibit apoptosis [25].…”

Section: Introductionmentioning

confidence: 96%

Chiral characterization of deprenyl‐N‐oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine

2003

View full text Add to dashboard Cite

A chiral capillary electrophoresis method has been developed for the simultaneous separation of the enantiomers of deprenyl and eight of its metabolites, among them the recently described metabolite deprenyl-N-oxide. Although heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) was suitable for the enantioresolution of deprenyl and its dealkylated derivatives, the enantiomers of deprenyl-N-oxide were just partly resolved. Carboxymethyl-beta-cyclodextrin (CMBCD) in as low as 2 mM concentration was capable of the enantiomer separation of all the nine examined compounds, however co-migration of 1R,2S-(-)-norephedrine and 1R,2R-(-)-pseudoephedrine, as well as 1S,2R-(+)-ephedrine and R-(-)-amphetamine was observed. This problem could be overcome by the use of a dual cyclodextrin system containing 4 mM DIMEB in addition to 2 mM CMBCD; simultaneous separation of all the compounds could be achieved. The optimized method was used for the analysis of rat urine samples after 10 days of treatment of animals with either R-(-)- or S-(+)-deprenyl. The stereospecific biotransformation of both deprenyl enantiomers was confirmed, and the stereoselectivity of N-oxide formation was demonstrated.

show abstract

“…R-amphetamine and R-methamphetamine without propargyl groups lose their neuroprotective effects and increase the apoptotic activity. This complication consists of a limitation of selegiline in clinical application (Haberle et al 2001;Szende et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes

et al. 2011

View full text Add to dashboard Cite

Selegiline (R-deprenyl), a monoamine oxidase-B (MAO-B) inhibitor, has complex pharmacological effect that contributes to treatment of neurodegenerative diseases such as Parkinson's and presumably Alzheimer's disease and might work as an inhibitor of tumor growth. In respect of tumorigenesis and metastasis formation, the controlled modifications of adhesion and migration have high therapeutic significance. In the present study, our purpose was to investigate cell physiological responses (adhesion, chemotaxis and proliferation) induced by selegiline, its metabolites and synthetic derivatives and to find some correlations between the molecular structure and the reported antitumor behavior of the derivatives. Our results demonstrated that both R- and S-deprenyls have the potency to elicit increased adhesion and a chemorepellent activity in monocyte model (Mono Mac 6 cell line derived from monoblastic leukemia); however, only the R-enantiomer proved to be cytotoxic. Among the metabolites R-amphetamine has retained the adhesion inducer and the chemorepellent effect of the parent drug on the most significant level. In contrast, a reversed chemotactic effect and an improved cytotoxic character were detected in the presence of fluoro group (p-fluoro-S-deprenyl). In summary, the adhesion inducer activity, chemorepellent and advantageous cytotoxic effects of selegiline and some derivatives indicate that these drug molecules might have inhibitory effects in metastasis formation in primary tumors.

show abstract

The effect of low oral doses of (?)-deprenyl and its metabolites on DSP-4 toxicity

Cited by 7 publications

References 21 publications

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

Chiral characterization of deprenyl‐N‐oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine

Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes

Contact Info

Product

Resources

About