Background: Growing pieces of evidence demonstrate a close relationship between type 2 diabetes (T2D) and neurodegenerative disorders such as Alzheimer’s disease. The similarity of physiological and pathological processes occurring in pancreatic β-cells and neurons over the course of these pathologies allows raising the question of the practicability of studying neuroprotective substances for their potential antidiabetic activity.Objective: This review analyzes studies of antidiabetic and cytoprotective action on pancreatic β-cells of the neuroprotective compounds that can attenuate the oxidative stress and enhance the expression of neurotrophins: low-molecular-weight NGF mimetic compound GK-2, selective anxiolytic afobazole, antidepressants lithium chloride, and lithium carbonate on the rat streptozotocin model of T2D.Results: It was found that all the above-listed neuroprotective substances have a pronounced antidiabetic activity. The decrease in the β-cells number, the average area of the pancreatic islets, as well as the violation of their morphological structure caused by the streptozotocin was significantly weakened by the therapy with the investigated neuroprotective substances. The extent of these morphological changes clearly correlates with the antihyperglycemic effect of these compounds.Conclusion: The presented data indicate that the neuroprotective substances attenuating the damaging effect of oxidative stress and neurotrophins deficit cannot only protect neurons but also exert their cytoprotective effect towards pancreatic β-cells. These data may provide a theoretical basis for the further study of neuroprotective drugs as potential therapeutic options for T2D prevention and treatment.

BACKGROUND: The non-immunogenic staphylokinase is a recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and fibrin selectivity approved in Russia for the acute ischemic stroke (AIS) thrombolytic therapy within 4.5 hours after symptom onset. We evaluated safety and efficacy outcomes of the non-immunogenic staphylokinase usage in patients with AIS in the Fortelyzin Population Investigation registry. METHODS: Between March 2021 and October 2024, patients with AIS treated with the non-immunogenic staphylokinase were enrolled in the prospective, open-label, internet-based, monitored, observational Fortelyzin Population Investigation registry. Demographics, risk factors, baseline stroke severity (defined by National Institutes of Health Stroke Scale), and onset to treatment time were recorded. Safety outcomes included symptomatic intracerebral hemorrhage (according to the ECASS III [European Cooperative Acute Stroke Study III] and SITS-MOST [Safe Implementation of Thrombolysis in Stroke—Monitoring Study] criteria) within 36 hours and all-cause mortality on day 90. Efficacy outcome was evaluated by functional independence using of modified Rankin Scale score of 0 to 2 on day 90. RESULTS: A total of 17 636 patients with AIS were treated with the non-immunogenic staphylokinase in 329 centers participated in the Fortelyzin Population Investigation registry during the study period (median age 68 [60–75]; 56% male; median baseline National Institutes of Health Stroke Scale score, 11 [8–16] points; median onset to treatment time, 2.4 hours [1.8–3.1]). The rate of symptomatic intracerebral hemorrhage according to the ECASS III criteria was 2% (356/17 636; 1.8–2.2), to the SITS-MOST criteria, 2% (330/17 636; 1.8–2.1). All-cause mortality on day 90 was 9% (1588/17 636; 8.6–9.4). The number of patients with a modified Rankin Scale score of 0 to 2 on day 90 was 61% (10 799/17 636; 60.5–61.9). These safety and efficacy outcomes were comparable with FRIDA (Fortelyzin Randomized Investigation Compared With Alteplase) randomized clinical trial results. CONCLUSIONS: The presented data suggest that intravenous thrombolysis with the non-immunogenic staphylokinase is safe and effective in routine clinical practice when used within 4.5 hours of AIS symptoms onset. These findings should encourage the wider usage of thrombolytic therapy with the non-immunogenic staphylokinase for suitable patients. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06707987.

We investigated the cytoprotective effect of a novel low-molecular-weight NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine), on pancreatic -cells. The neuroprotective effect of GK-2 had been previously shown to be associated with selective activation of the PI3K/Akt signaling pathway. In this study, rats with streptozotocin (STZ)-induced type 2 diabetes mellitus were used. Metformin was used as a reference drug. STZ was immunohistochemically demonstrated to reduce the number of -cells and affect their morphological structure. Treatment of diabetic animals with GK-2 (at a dose of 0.5 mg/kg intraperitoneally or 5 mg/kg orally) or metformin (300 mg/kg orally) for 28 days reduced the damaging effect of STZ. The effect of GK-2 on manifestations of STZ-induced diabetes, such as hyperglycemia, weight loss, polyphagia, and polydipsia, was comparable to that of metformin, while the cytoprotective activity of GK-2 was slightly stronger than that of metformin. A strong positive correlation between morphometric parameters and the blood glucose level was revealed. The GK-2 cytoprotective effect on -cells is supposed to manifest through the PI3K/Akt signaling pathway.

The aim. To study possible allergenic and immunotoxic properties of the recombinant non-immunogenic staphylokinase molecule with the amino acids replacement Lys₇₄, Glu₇₅ and Arg₇₇ with alanine in preclinical and clinical studies.Materials and methods. The allergenic and immunotoxic properties of the recombinant non-immunogenic staphylokinase drug were studied using standard methods in accordance with the Guidelines for the Preclinical Study of New Substances in guinea pigs (n=15) and mice (n=45) at doses 5, 10 and 20 times higher than therapeutic (for humans). A clinical study was conducted in 100 patients with acute ST-segment elevation myocardial infarction after a single intravenous injection of the drug. The study included the determination of titers of specific antibodies to recombinant non-immunogenic staphylokinase and the study of plasma neutralizing activity.Results. During the complete set of preclinical studies, it was found that the drug does not affect the cellular and humoral immune response in guinea pigs and mice at doses many times higher than therapeutic doses for humans. It was found that the drug did not cause an immediate-type of hypersensitivity reaction (Weigle index 0) and a delayed type IV (0 points according to S.V. Suvorov) in guinea pigs, did not affect the cellular capacity of popliteal lymph nodes (reaction index 0.91), did not affect the number of nucleated and antibody-forming cells in the spleen of mice. As a result of a clinical study of recombinant non-immunogenic staphylokinase, no allergic reactions were registered. Assessment of the neutralizing activity of the plasma of patients who were administered recombinant non-immunogenic staphylokinase showed that 70% samples did not have neutralizing activity: 30% of the patients’ samples were characterized by a minimum neutralizing activity of 0.33±0.02 μg/mL, which is 30–310 times lower than after the use of native staphylokinase. These values are 7.8 times lower than the determined concentration of recombinant non-immunogenic staphylokinase in the blood (2.59 μg/mL). Thus, the drug does not lead to the anti-staphylokinase neutralizing antibodies formation capable to neutralize its effect upon repeated administration.Conclusion. According to the results of the trials, the absence of allergenic and immunotoxic properties of the recombinant non-immunogenic staphylokinase and its safety in relation to the immune system have been proven.

Aim. To assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with massive pulmonary embolism and hemodynamic instability. Non-immunogenic staphylokinase is a modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity and fibrin selectivity.Material and methods. This multicenter, open-label, randomized, comparative clinical trial FORPE in two parallel groups was conducted in 23 clinical centers in Russia. A total of 310 patients aged 18 years and older with hemodynamic instability and computed tomography pulmonary angiography verified massive pulmonary embolism and right ventricular dysfunction were included. The patients were randomly assigned in either non-immunogenic staphylokinase (15 mg) or alteplase (100 mg) group. Both medicines were administered intravenously. An independent biostatistician created a randomization sequence using computer-generated random numbers. Randomization was performed using the envelopes. The study was open-label, and emergency unit staff, investigators, and patients were informed about the assigned drug. The primary efficacy endpoint was 7-day all-cause death after randomization. The non-inferiority margin was set at 10% for the difference in 7-day all-cause mortality after randomization between the compared groups. Non-inferiority was tested using the Welch t-test for the primary efficacy endpoint. Secondary efficacy endpoints were analyzed in both the intention-to-treat and per-protocol populations.Results. Of 348 patients screened between December 25, 2020, and July 31, 2023, 310 (89%) were included in the study. Of the total number, 155 (50%) patients were randomized to the non-immunogenic staphylokinase group and 155 (50%) to the alteplase group. In the non-immunogenic staphylokinase group, the primary efficacy endpoint, 7-day all-cause death, was 2% in the intent-to-treat population and 2% in the per-protocol population, whereas in the alteplase group it was 3% (odds ratio (OR) 0,75, 95% confidence interval (CI) 0,11-4,49; p=1,00) and 3% (OR 0,75, 95% CI 0,11-4,52; p=1,00), respectively. The difference in the primary efficacy endpoint was 0,6% (95% CI -2,8 to -4,0) in the intent-to-treat population and 0,6% (95% CI -2,9 to -4,2) in the per-protocol population. Thus, the lower limit of the 95% CI did not cross the non-inferiority margin (p<0,001). There were no cases of hemorrhagic stroke in the non-immunogenic staphylokinase group, whereas there were three cases (2%) of hemorrhagic stroke in the alteplase group (p=0,25). Serious adverse events were experienced by 11 patients (7%) in the non-immunogenic staphylokinase group compared with 12 patients (8%) in the alteplase group (p=1,00).Conclusion. Non-immunogenic staphylokinase is at least as effective as alteplase in the treatment of patients with massive pulmonary embolism with hemodynamic instability and has a higher safety profile. Future observational studies of non-immunogenic staphylokinase are needed to continue assessing its safety and efficacy. Given the high safety and efficacy of non-immunogenic staphylokinase, its use should be studied in patients with moderate-to-high risk pulmonary embolism.