Current Pharmaceutical Design - Volume 29, Issue 2, 2023

About 2.8% of the global population are being suffered from Diabetes mellitus. Diabetes mellitus is a group of metabolic disorders that is characterized by an absolute lack of insulin and resulting in hyperglycemia. To overcome the challenges, many antidiabetic drugs are being used, and research is being carried out in search of more effective anti-diabetic drugs. To study the effectiveness of antidiabetic drugs, many diabetic models, chemicals, and diabetogenic hormones were used at the research level. In this review, we summarised various animal models used, chemicals that induce diabetes, their properties, and the mechanism of action of these models. Further, diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic manipulations. To better understand both the pathogenesis and potential therapeutic agents, appropriate animal models of type 1 & type 2 diabetes mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of diabetes in humans. The use of the appropriate animal model based on these similarities can provide much-needed data on pathophysiological mechanisms operative in human diabetes.

Currently, many therapeutic drugs are difficult to cross the blood-brain barrier (BBB), making it difficult to reach the site of action and thus fail to achieve the desired efficacy. In recent years, researchers and drug designers have increasingly focused on nanotechnology to break through the difficulty of small molecule inhibitors to cross the blood-brain barrier (BBB) and improve the success rate of drug delivery to the central nervous system. Among the common central neurological diseases, such as encephalitis, Parkinson's, Alzheimer's disease, and epilepsy, Alzheimer's disease has attracted much attention from researchers. Alzheimer's disease is a specific neurodegenerative disease, which causes irreversible degeneration of neurons as well as synapses in the brain, resulting in memory and cognitive dysfunction, along with other psychiatric symptoms and behavioral disorders, which seriously affects people's everyday life. Moreover, nanotechnology has excellent potential for application in AD treatment. Studies have shown that nanocarriers can target the delivery of chemotherapeutic drugs, antioxidants, and other therapeutic substances to brain tissue using existing physiological mechanisms, thus effectively alleviating the disease progression of AD. Therefore, various nanoparticles and nanomedicine have been developed and constructed for diagnosing and treating AD in the past decades, such as nanoparticles, bionanoparticles, liposomes, nano-gel, dendrimers, and self-assembled nanoparticles. This study aims to review the applications and results of nanotechnology in the treatment of Alzheimer's disease in recent years and provide some ideas and clues for future research and development of more effective drug delivery systems.

Polymeric micelles have opened up new horizons for improving drug delivery to brain particularly due to their small size, long circulation time, good stability and targetability. They are used to treat a variety of brain conditions, including glioblastoma, migraine, Alzheimer's, Parkinson's, and other conditions linked to the brain. Micelles are currently underutilised in brain targeting despite having several benefits and spanning a wide variety of brain illnesses. Since most medications are unable to cross the blood brain barrier, scientists are continuously working to discover efficient solutions to the problems. The most pressing issue was thought to be the viability and difficulties of translating micelles into the therapeutic setting. This review describes the role of micellar delivery system in brain diseases treatment along with their route of administration and outcomes. The review also discusses the current state of patents and clinical trials in the relevant fields and their potential future applications.

Background: A dipeptide mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, GSB-106, was designed and synthesized by V.V. Zakusov Research Institute of Pharmacology. The compound activated in vitro TrkB, MAPK/ERK, PI3K/AKT, and PLCγ, like full-length BDNF. In vivo, GSB-106 exhibited antidepressant-like, neuroprotective and neuroregenerative properties. The aim of this work was to study the effects of GSB-106 on depressive-like behavior, cognitive impairments, as well as on hippocampal neuroplasticity in an experimental model of ischemic stroke. Methods: Male Wistar rats were subjected to 60 minutes of transient middle cerebral artery occlusion (MCAO). Dipeptide GSB-106 was administered intraperitoneally at a dose of 0.1 mg/kg/day for 21 days after surgery. 30-40 days after MCAO, the depressive-like state in the forced swimming test and memory impairment in the novel object recognition test were assessed. Then, the content of CREB, as a neuroplasticity marker, was assessed in the ipsilateral hippocampus. Results: Rats in MCAO group showed depression-like behavior (increase in immobility time in the forced swimming test by 22% compared to sham group), impairments in short-term and long-term memory (decrease in the discrimination index in the novel object recognition test by 70% and 50%, respectively), and a decrease in immunoreactivity to CREB (cAMP response element-binding protein) in the hippocampus by 36% as compared with the sham group. GSB-106 completely prevented the behavior impairments and counteracted the reduction of immunoreactivity to CREB in the hippocampus. Conclusion: The BDNF dipeptide mimetic GSB-106 is promising for further development as a drug for the treatment of poststroke neuropsychiatric disorders.

Background: Percutaneous transluminal renal angioplasty (PTRA) with or without stenting is the gold standard therapy in patients with atherosclerotic renal artery stenosis (aRAS). However, therapeutic success depends on the correct timing of revascularization and the reversibility of the renal damage. Materials and Methods: We report a case series of patients treated with PTRA for renovascular hypertension and ischemic nephropathy. We measured bilateral renal resistive index (RRI), circulating renal stem cells (RSC), and Neutrophil Gelatinase Associated Lipocalin (NGAL) at baseline and after PTRA at different time points to understand their changes in post-revascularization. Results: At baseline, the studied patients (n = 5) had different RSC levels. After PTRAs, all patients showed an improvement in blood pressure, while renal function varied differently within the studied subjects. RRI > 0.75 at baseline and the absence of NGAL decrease after PTRAs were associated with post-PTRA renal function worsening, despite an increase of RSC in all patients. Conclusion: Although limited to a few patients, our observation allowed the exploration of the behaviour of the studied parameters in different degrees of renal ischemia. This revealed different disease models suggesting the importance of further investigations in larger and homogeneous cohorts to confirm that a greater basal RSC percentage, low RRI values before PTRA, and a post-revascularization NGAL reduction could be related to better renal outcomes in aRAS patients.

Background: The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes. Objective: To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology. Methods: We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity. Results: The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment. Conclusion: The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.

Background: The soluble urokinase plasminogen activator receptor (suPAR), a biomarker of inflammation, has been found to be a potential prognostic factor of renal function progression. Our previous study showed that plasma suPAR levels were significantly associated with disease activity and prognosis in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV). Objective: This study aimed to explore whether urokinase plasminogen activator receptor (uPAR) participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV. Methods: GEnC activation and injury were analyzed by measuring the mRNA levels of ICAM-1 and VCAM-1. Permeability experiments were performed to detect endothelial monolayer activation in number. The expression of TLR4 was detected. In addition, TLR4 siRNA and TLR4 inhibitors were employed to determine its role. Bioinformatics methods were used for further analysis. Results: Compared with a single stimulation, uPAR could further increase the expression of ICAM-1 and VCAM-1 mRNA levels, increase endothelial monolayer permeability and impair tight junctions in GEnCs stimulated with MPO-ANCA-positive IgG. The expression of TLR4 was upregulated by uPAR and MPO-ANCApositive IgG stimulation. TLR4 siRNA significantly reduced the expression of ICAM-1 and VCAM-1 mRNA levels induced by uPAR and MPO-ANCA-positive IgG. The TLR4 antagonist significantly downregulated the levels of ICAM-1 mRNA in cells and sICAM-1 in the supernatants of GEnCs treated with uPAR plus MPOANCA- positive IgG. PLAUR is a core gene in bioinformatics analysis. Conclusion: uPAR protein can enhance the GEnC activation and injury induced by MPO-ANCA-positive IgG through the TLR4 pathway, indicating that suPAR may be involved in the pathogenesis of AAV and that su- PAR might be regarded as a potential therapeutic target.