Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs.

Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP).

Aging-associated cognitive disorders lack proper medication. To meet this need translation-wise, modification of the animal models is also required. In the present study, effect of the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP, a deprenyl derivative) on age-related cognitive decline was investigated in experienced, aged Long-Evans rats.

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum.

The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((-)BPAP, ()-(-)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling.

Chronic treatment with enhancer drugs modifies the gene expression of selected parameters related to brain plasticity in rats under stress conditions.

Selegiline, also known as L-deprenyl, and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) were found to induce enhancement of monoamine neurotransmission in low and very low doses. In addition, these enhancers may modify glutamatergic neurotransmission. The aim of the present study was to test the hypothesis that under stress conditions, chronic treatment with enhancer drugs has a positive impact on the glutamatergic system and other parameters related to brain plasticity, stress-related systems, and anxiety behavior.

Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice.

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects.

Geroprotection in the future. In memoriam of Joseph Knoll: The selegiline story continues.

In memoriam of Joseph Knoll: the selegiline story continues.

Synthetic enhancer compounds, besides acting on biogenic amine system, influence the glutamate transmission and stress response.

Pharmaceutically available enhancer selegiline/(-)-deprenyl (DEP) in the clinically used dose shows antidepressant effect, but nothing is known about this effect in enhancer dose, and its effect on co-morbid anxiety. Moreover, data about the antidepressant/antianxiety effects of the serotonin-influencing enhancer, (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) are also missing. The aim of the present paper is to establish the role of enhancer regulation in anxiety and follow the changes in the phosphorylation of glutamate subunits in prefrontal cortex as well as stress-related organ and hormonal changes as possible background mechanism.

Inhibitory Effect of (2R)-1-(1-Benzofuran-2-yl)-N-propylpentan-2-amine on Lung Adenocarcinoma.

BPAP is a potent enhancer substance with catecholaminergic and serotoninergic activity in the brain. It was discovered that it is also effective against certain types of experimental cancers, showing the most promising results in case of lung cancer. That is why we tested its efficacy in two different doses in a newly developed EGFR wild type mouse lung adenocarcinoma xenograft model.

A longevity study with enhancer substances (selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain.

Aims: First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first β-phenylethylamine (PEA)-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations.

Main Methods: Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats.

Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP).

Aims: The first longevity study demonstrating that rats treated with the MAO-B inhibitory dose of (-)-deprenyl (0.25mg/kg) lived significantly longer than their saline-treated peers was published in 1988, and corroborated in many papers. The recent findings that (-)-deprenyl is primarily a PEA-derived synthetic catecholaminergic activity enhancer substance; (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) is a tryptamine-derived synthetic enhancer substance, initiated our first longevity study on rats with low enhancer doses of (-)-deprenyl and BPAP to test the enhancer effect's role in life extension.

The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015).

Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive disorder; and used as an anti-aging drug, achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO-B). The demonstration that the DEP analog (-)-1-phenyl-2-propylaminopentane devoid of MAO inhibitory property, enhanced like DEP the activity of the catecholaminergic brain engine revealed that this effect is unrelated to the selective inhibition of MAO-B. β-Phenylethylamine (PEA), the important trace-amine in the mammalian brain, is known to be a releaser of catecholamines.

[The role of alpha-synuclein in Parkinson's disease].

α-synuclein, a small protein (140 amino acids) encoded by the SNCA gene is the best known isoform of the synuclein protein family. Though its physiological role is still not fully clarified, there is growing experimental evidence for a causal role of α-synuclein in the so-called conformational-neurodegenerative diseases. Conformational changes in the structure of the native soluble protein form insoluble neurotoxic aggregates and finally contribute to the formation of inclusion Lewy-bodies and Lewy-neurites.

[The role of parkin in Parkinson's disease].

Parkin (Parkinson juvenile disease protein 2) is a ~52 kDa (426 amino acid) enzyme protein, encoded by PARK2 gene and located on the 6q chromosome. It plays an important role in the ubiquitin-proteasome system and acts as a regulator of protein breakdown. Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface and induces the degradation of various membrane proteins which are candidates for mitophagia.

Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline.

Background: (-)-Deprenyl and rasagiline are classified as selective inhibitors of B-type MAO. The DATATOP study revealed that the administration of (-)-deprenyl to untreated patients with Parkinson's disease (PD) significantly delays the need for levodopa therapy (Parkinson Study Group, 1989). Rasagiline was ineffective in this respect (Parkinson Study Group, 2002).

[Guidelines on the pharmacotherapy of the dental patient during pregnancy].

Physiological differences occuring in pregnancy modify certain steps of dental treatments. Since in our everyday practice we meet expectant patients, we have to be aware of what kind of changes does this transitional state require from the dentist, how to do a good timing in the course of dental treatment, which are those medicaments that can be used safely and those which should be avoided. The summerized data in the article are to contribute the safe choice of the possibly necessary antibiotics during the treatments.

[The feasibility of synthetic enhancer substances for preventive nanotherapy].

Nanotechnology, the great promise of the 21st century, may revolutionize also the art of healing. Previously unexpected broadening of diagnostic procedures and methods to deliver specific drugs acting in lower than nanomolecular concentrations right to the target cells may play a crucial role in the rapid development of preventive medicine. In this context, (-)-deprenyl/selegiline, a drug developed 40 years ago and still world-wide used to treat Parkinson's disease, Alzheimer's disease and depression, by enhancing the activity of catecholaminergic neurons in the brain stem via a previously unknown mechanism [catecholaminergic activity enhancer (CAE) effect], is a highly promising experimental tool for further research in this direction.

[Slowing the age-induced decline of brain function with prophylactic use of (-)-deprenyl (Selegiline, Jumex). Current international view and conclusions 25 years after the Knoll's proposal].

Due primarily to developments in immunology, chemotherapy and hygiene the estimated life expectancy at birth increased during the last century from about 55 years to 80 years. Since the human Technical Life Span (TLSh) is about 120 years and life expectancy is today steadily increasing by about 2.2 months/year, a life span of 100 years may appear quite soon.

[A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508].

N-methylpropargylamine-1-aminoindane (J-508), a strong releaser of catecholamines was described 30 years ago as a more potent selective inhibitor of MAO-B than (-)-deprenyl (Knoll 1978). In 2007 the desmethyl-analogue of J-508 (rasagiline) was registered as a new selective inhibitor of MAO-B and a possible substitute for (-)-deprenyl in therapy. The discovery of the enhancer regulation, the realization that catecholaminergic and serotonergic neurons in the brain stem are enhancer-sensitive neurons, phenylethylamine (PEA) and triptamine are endogenous enhancer substances, (-)-deprenyl is a PEA-derived synthetic enhancer substance, and finally the development of (-)-BPAP, a tryptamine-derived, 100 times more potent synthetic enhancer substance than (-)-deprenyl, made it clear that the enhancer effect of (-)-deprenyl is primarily responsible for the therapeutic benefits of this drug.

The use of the synthetic enhancer substances (-)-deprenyl and (-)-BPAP in major depression.

There is still a great need for the development of antidepressants with a new pharmacological spectrum. The finding that phenylethylamine and tryptamine are endogenous enhancers of the impulse propagation mediated release of catecholamines and serotonin in the brain, and the development of synthetic mesencephalic enhancer substances opened the possibility to stimulate catecholaminergic and serotonergic neurons in the mesencephalon via a previously unknown mechanism. (-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons.

Treatment possibilities of Alzheimer's disease.

A brief summary of the current treatment of Alzheimer disease (AD) (cholinergic replacement therapy, influence of glutamatergic neurotransmission, treatment based on the beta-amyloid cascade theory, antioxidants, anti-inflammatory drugs) clearly proves that the applied strategies are practically inefficient. We describe therefore the rationale and design of a reasonable clinical trial to test the validity of Knoll's concept that the administration of a synthetic mesencephalic enhancer substance prior to the precipitation of the symptoms is our only chance to significantly reduce the prevalence of the two main neurodegenerative disorders AD and Parkinson's disease (PD). Considering that in the population over 65 there are substantial sex (68% female, 32% male) and geographical (highest rate: 10% in USA) differences in the incidence of AD, we propose to perform the clinical trial in 75-85 year old females in the USA.

Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives.

The discovery of enhancer regulation in the mesencephalon and the concept that it plays a key role in the operation of innate and acquired drives [Neurochem. Res. 28 (2003) 1187] sets the trace amines (TAs) in their true physiological perspective.

An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats.

The recent discovery of the enhancer regulation in the mammalian brain brought a different perspective to the brain-organized realization of goal-oriented behavior, which is the quintessence of plastic behavioral descriptions such as drive or motivation. According to this new approach, 'drive' means that special endogenous enhancer substances enhance the impulse-propagation-mediated release of transmitters in a proper population of enhancer-sensitive neurons, and keep these neurons in the state of enhanced excitability until the goal is reached. However, to reach any goal needs the participation of the catecholaminergic machinery, the engine of the brain.