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

Knoll, J.; Baghy, Kornélia; Eckhardt, S.; Ferdinándy, Péter; Garami, Miklós; Hársing, László G.; Hauser, Péter; Mervai, Zsolt; Pócza, Tímea; Schaff, Zsuzsa; Schüler, D.; Miklya, Ildikó

doi:10.1016/j.lfs.2017.06.010

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…CAE compounds made it possible to analyze the enhancer regulation of the neurochemical transmission in the brain and led to identifying their role in life expectancy [ 30 , 31 ], tumor genesis [ 32 , 33 ], and psychiatric diseases such as depression, mood disorders, and stress-related anxiety [ 34 , 35 , 36 ]. (−)BPAP was extensively investigated in a number of behavioral and longevity studies, and its antitumor effect has also been demonstrated [ 31 , 32 ]. The potential uses of (−)BPAP in these clinical indications are believed to relate to its CAE effects.…”

Section: Introductionmentioning

confidence: 99%

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum

Hársing

Knoll

Miklya

2022

IJMS

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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, (R)-(−)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [3H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent manner, whereas (−)BPAP potentiated [3H]dopamine release with vesicular origin via TAAR1 mediation. (−)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (−)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (−)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (−)BPAP also increased VMAT2 operation enforcing vesicular [3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (−)BPAP is linked to the activation of TAAR1 and the signal transduction attached.

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Section: Introductionmentioning

confidence: 99%

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum

Hársing

Knoll

Miklya

2022

IJMS

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“…Despite no overall effect on general locomotion, the enhancer drugs, in specific enhancer concentrations significantly reduced the activity-induced elevation in the main stress hormone. Considering the beneficial effects of the enhancer drugs (prolongation of lifespan [7], suppression of tumor manifestation [13]), we might assume that this smaller circadian elevation of corticosterone might be one of the mechanisms contributing to the beneficial effects of prolonged enhancer treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Previous results using both non-specific [12] and specific enhancer concentrations [7] confirmed that DEP as well as BPAP significantly extend the lifespan of different mammalian species and reduce tumor manifestation [13]. However, these studies suggested that the enhancer regulation may not be exclusive to the biogenic amine system.…”

Section: Introductionmentioning

confidence: 95%

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

Knoll

Zelena

Tı́már

et al. 2020

Behavioural Brain Research

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“…Both molecules exhibited a lifespanextending effect, but BPAP showed more promising results [10]. It was noticed that significantly less spontaneous fibrosarcomas developed in the treated groups than in the control group [11]. Based on these observations, we tested the effects of lowdose BPAP treatment in different tumor models.…”

Section: Introductionmentioning

confidence: 99%

“…In an in vivo model of colon cancer with liver metastasis, BPAP significantly reduced the number of metastasis [11]. In addition, BPAP was tested in other tumor models as well: xenograft models of mouse colon carcinoma and lung adenocarcinoma and in a primary hepatocarcinogenesis experiment induced by diethylnitrosamine in mice.…”

Section: Introductionmentioning

confidence: 99%

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

Mervai

Reszegi

Miklya

et al. 2019

Pathol. Oncol. Res.

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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. Experiments were conducted on FVB/N and SCID mouse strains treated with low and high dose of BPAP. Body weight, survival, and tumor volumes were recorded. Furthermore, the activity of major signaling pathways of NSCLC such as MAPK and Akt/mTOR as well as cell cycle regulation were determined. Significant inhibition of tumor growth was exerted by both doses, but the mechanism of action was different. High dose directly inhibited, whereas low dose activated the main signaling pathways. Exposure to low dose BPAP resulted in elevated activity of the mTOR pathway together with p16 INK -induced cell cycle arrest, a typical feature of geroconversion, a senescent state characterized by loss of cell proliferation. Finally the events culminated in cell cycle inhibition point in case of both doses mirrored by the decrease of cyclin D1, CDK4 and PCNA. In addition, BPAP treatment had a beneficial effect on bodyweight suggesting that the compound at least in part is able to compensate the cancer-related wasting. In view of the low toxicity and confirmed antitumor effect of BPAP against experimental lung adenocarcinoma, this novel compound deserves further attention.

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

Cited by 6 publications

References 26 publications

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum

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

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

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