Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats

Tékus, Valéria; Horváth, Ádám; Csekő, Kata; Szabadfi, Krisztina; Kovács-Valasek, Andrea; Danyadi, B.; Deres, László; Halmosi, Róbert; Sághy, Éva; Varga, Zoltán V.; Adeghate, Ernest; Kőszegi, Tamás; Mátyus, Péter; Gábriel, Róbert; Ferdinándy, Péter; Pintér, Erika; Helyes, Zsuzsanna

doi:10.1016/j.biopha.2020.111105

Cited by 11 publications

(8 citation statements)

References 78 publications

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“…Whether the in vitro SSAO-mediated insulin-like effect of Bza is solely responsible for the antihyperglycemic effect of Bza drinking is far from being demonstrated here. However, this assumption agrees with the conclusions of independent studies showing that treatment of diabetic rodents with SSAO inhibitors prevents diabetic complications but is not antihyperglycemic at all[ 43 - 45 ]. All these observations bring evidence that adipose cells are predominantly involved in Bza oxidation, as a consequence of their high SSAO expression[ 3 ], although they do not rule out other concomitant mechanisms.…”

Section: Discussionsupporting

confidence: 90%

Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation

Carpéné¹,

Atanasov²,

Les³

et al. 2022

WJD

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BACKGROUND Benzylamine (Bza) oral administration delays the onset of hyperglycemia in insulin-resistant db -/- mice; a genetic model of obesity and type 2 diabetes. AIM To extend the antihyperglycemic properties of oral benzylamine to a model of insulin-deficient type 1 diabetes. METHODS Male Swiss mice were rendered diabetic by streptozotocin treatment (STZ) and divided in two groups: one received 0.5% Bza as drinking solution for 24 d (STZ Bza-drinking) while the other was drinking water ad libitum . Similar groups were constituted in age-matched, nondiabetic mice. Food intake, liquid intake, body weight gain and nonfasting blood glucose levels were followed during treatment. At the end of treatment, fasted glycemia, liver and white adipose tissue (WAT) mass were measured, while glucose uptake assays were performed in adipocytes. RESULTS STZ diabetic mice presented typical features of insulin-deficient diabetes: reduced body mass and increased blood glucose levels. These altered parameters were not normalized in the Bza-drinking group in spite of restored food and water intake. Bza consumption could not reverse the severe fat depot atrophy of STZ diabetic mice. In the nondiabetic mice, no difference was found between control and Bza-drinking mice for any parameter. In isolated adipocytes, hexose uptake was partially activated by 0.1 mmol/L Bza in a manner that was obliterated in vitro by the amine oxidase inhibitor phenelzine and that remained unchanged after Bza supplementation. Oxidation of 0.1 mmol/L Bza in WAT was lower in STZ diabetic than in normoglycemic mice. CONCLUSION Bza supplementation could not normalize the altered glucose handling of STZ diabetic mice with severe WAT atrophy. Consequently, its antidiabetic potential in obese and diabetic rodents does not apply to lipoatrophic type 1 diabetic mice.

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Section: Discussionsupporting

confidence: 90%

Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation

Carpéné¹,

Atanasov²,

Les³

et al. 2022

WJD

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“…Meanwhile, we collated information on certain drugs being investigated for the treatment of DR, including anti-angiogenic, anti-vascular leakage, anti-inflammatory, anti-oxidative damage, and neuroprotective agents ( Table 5 ). Some of these drugs play multiple roles in the treatment of DR. For example, melatonin and SZV1287 have both anti-inflammatory and antioxidant effects ( Tu et al, 2021b ; Tekus et al, 2021 ). The pathogenesis of DR is complex, therefore, multi-targeted drugs may be more effective.…”

Section: Treatmentsmentioning

confidence: 99%

Diabetic retinopathy: Involved cells, biomarkers, and treatments

et al. 2022

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Diabetic retinopathy (DR), a leading cause of vision loss and blindness worldwide, is caused by retinal neurovascular unit dysfunction, and its cellular pathology involves at least nine kinds of retinal cells, including photoreceptors, horizontal and bipolar cells, amacrine cells, retinal ganglion cells, glial cells (Müller cells, astrocytes, and microglia), endothelial cells, pericytes, and retinal pigment epithelial cells. Its mechanism is complicated and involves loss of cells, inflammatory factor production, neovascularization, and BRB impairment. However, the mechanism has not been completely elucidated. Drug treatment for DR has been gradually advancing recently. Research on potential drug targets relies upon clear information on pathogenesis and effective biomarkers. Therefore, we reviewed the recent literature on the cellular pathology and the diagnostic and prognostic biomarkers of DR in terms of blood, protein, and clinical and preclinical drug therapy (including synthesized molecules and natural molecules). This review may provide a theoretical basis for further DR research.

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“…administration [19,20]. Furthermore, we demonstrated its beneficial effects in a chronic insulin-controlled diabetes model including protection against streptozotocin-induced beta cell damage and some microvascular complications, such as neuropathy and retinopathy [23].…”

Section: Discussionmentioning

confidence: 75%

“…For this study, it was provided as previously described [9]. Physicochemical characteristics of SZV 1287 and its metabolites including nuclear magnetic resonance (NMR) and mass spectrometry data, as well as the melting point were previously published [23,24].…”

Section: Synthesis Of Szv 1287mentioning

confidence: 99%

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain

et al. 2021

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SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.

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Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats

Cited by 11 publications

References 78 publications

Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation

Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation

Diabetic retinopathy: Involved cells, biomarkers, and treatments

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain

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