Chrysin loaded nanovesicles ameliorated diabetic peripheral neuropathy. Role of NGF/AKT/GSK-3β pathway

Diabetes mellitus (DM) is a broad term that refers to a variety of metabolic disorders characterized by the occurrence of hyperglycemia as a result of impaired insulin secretion, insulin action, or both [1]. World health Organization (WHO) stated that, diabetes affects nearly 3% of the world's population and is anticipated to reach 6% by 2025 [2]. Noteworthy, Egypt is among the top ten nations in the world in terms of diabetic patients. According to the International Diabetes Federation (IDF) from 2013 to 2035, the number of diabetic patients in the Middle East and North Africa (MENA) region is predicted to increase by 96%, from 34.6 million to 67.9 million [3]. DM can result in a wide variety of complications affecting the cardiovascular, neurological, renal, and other body systems [4].

Diabetic neuropathy is a group of disorders that affect various parts of the nervous system independently or in combination. It affects pain fibers, motor neurons, and the autonomic nervous system [5]. Peripheral neuropathy is the most common consequence of diabetes, with an overall prevalence of 50–60% [6]. Clinically, allodynia, hyperalgesia, and spontaneous pain are the main characteristics of diabetic peripheral neuropathy (DPN) [7]. Chronic DPN symptoms can endure for years and significantly reduce the quality of life, resulting in anxiety, depression, and other psychological issues [8].

Various factors account for the development of DPN, including metabolic problems, microvascular damage, deficit in neurotrophic support, changes in neuro-immune interactions, inflammation and neural cell apoptosis [9]. It is well known that the majority of these factors are caused by increased oxidative stress, due to auto-oxidative glycosylation, overproduction of advanced glycation end products, and activated polyol pathway following hyperglycemia [10].

Nerve growth factor (NGF) is one of the most abundant growth factors of the neurotrophin family [5]. It is a crucial factor involved in the development, survival, and plasticity of peripheral sympathetic neurons [11]. The role of nerve growth factor/protein kinase B/glycogen synthase kinase 3β (NGF/AKT/GSK-3β) signaling pathway in mediating neuronal cell growth, survival, proliferation, and death has been implicated in diabetic peripheral neuropathy [12].

Pharmacological management of DPN is still challenging. It is associated with various side effects, inadequate pain relief and poor patient adherence [13]. Flavonoids have been reported to be safe natural alternative therapeutics for management of DPN [14,15].

Chrysin (CHY) is a flavonoid that naturally found in propolis, honey, and a variety of plant extracts [16]. CHY has long been utilized as a health supplement [17]. However, prior research studies indicated that CHY possesses a number of significant pharmacological effects, including anti-inflammatory, immunoregulatory, antioxidant, anticancer, and antiviral capabilities [[18], [19], [20]]. A number of studies have shown that CHY inhibits pro-inflammatory cytokine expression and histamine release, downregulates nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS) [21], upregulates apoptotic pathways [18], and demonstrated a potent anti-glycemic activity [22]. However, due to its hydrophobicity, poor solubility, extensive liver first pass effect, CHY has poor oral bioavailability. So efforts have been directed towards the use of nanoformulations of CHY, in an attempt to improve its bioavailability [23,24].

Nanovesicles (NVs) are highly adaptable and promising systems for the transport and/or targeting of drugs and flavonoids [25,26]. Vesicles, are self-assembled structures composed of a single or multiple concentric bilayers containing lipid or phospholipid in their composition which surround an aqueous core, have been widely implicated in biomedical applications [27]. Regarding their built-in lipophilicity and small particle size, these NVs may be able to increase the extent of drug absorption after oral administration by bypassing hepatic uptake and metabolism [28,29]. In this study, lipoid S45, a soybean lecithin containing 45% phosphatidylcholine with a proved efficiency of forming vesicles [30], was used to prepare NVs containing fatty acids in presence of Brij 78 (polyoxymethylene 20 stearyl ether) in order to be a promising carrier for CHY.

Although the anti-nociceptive effect of CHY has been previously assessed [31], the precise mechanism underlying such effect needs to be investigated. So, this work aims to assess the effectiveness of CHY and lecithin NVs, as a potential oral drug delivery system, for CHY encapsulation aiming to improve its solubility and hence its oral bioavailability in STZ-induced DPN in rats. Furthermore, the role of hyperglycemia, oxidative stress biomarkers, NGF/AKT/GSK-3β pathway, and apoptosis was investigated in this pathological condition.

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