ALZHEIMER’S DISEASE: DELIVERY OF DRUGs THROUGH INTRANASAL ROUTE

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairments. A major histopathological hallmark of AD is the presence of amyloid deposits in the parenchyma of the amygdala, hippocampus, and neocortex. β-amyloid is a small piece of a larger protein called “amyloid precursor protein†(APP). The main component of amyloid is the β-Amyloid protein (Aβ), a 39.43 amino acid peptide composed of a portion of the transmembrane domain and the extracellular domain of the APP. Aβ deposition leads to synaptic degeneration and interacts with different types of central nervous system receptors; hence, it disrupts neuronal homeostasis. Moreover, Aβ deposition along the cerebral vessels alters their tonicity and triggers some of the cerebrovascular deficits. Furthermore, its accumulation disrupts intracellular Ca2+ homeostasis which ultimately reduces neuronal Ca2+ buffering capacity and increases excitotoxicity outcomes. The emerging approach is to bypass the BBB by intranasal delivery, which provides a practical, noninvasive, rapid and simple method to deliver the therapeutic agents to the CNS. This method works the unique connection between the nose and the brain that has evolved to sense odors and other chemical stimuli. On the basis of clinical trials (Phase I and II) it is reported that the intranasal route is feasible for the transport of the drug to the CNS. Intranasal delivery does not require any modification of the therapeutic agents and does not require that drugs be coupled with any carrier like in case of drug delivery across the BBB. A wide variety of therapeutic agents, including both small molecules and macromolecules can be successfully delivered, including to the CNS, using the intranasal method.   Key Words: Alzheimer’s disease, β-amyloid, cerebrovascular deficits, excitotoxicit

Nrf2 inhibition induces oxidative stress, renal inflammation and hypertension in mice

Oxidative stress and renal inflammation play a pivotal role in the pathogenesis of hypertension. The redox-sensitive transcription factor, nuclear factor E2-related factor 2 (Nrf2) is the master regulator of phase II antioxidant enzymes that protects against oxidative stress and inflammation. This study aimed to investigate the effect of Nrf2 inhibition on oxidative stress-associated hypertension and renal dopamine 1 receptor (D1R) dysfunction in mice. Male C57BL/6 J mice were treated with a pro-oxidant, L-buthionine sulfoximine (BSO) (10 mmol/L in drinking water), and ML385 (10 kg body weight/kg body weight/day, intraperitoneally), a novel Nrf2 inhibitor that blocks Nrf2 regulated downstream target genes expression. Mice treated with BSO exhibited oxidative stress, renal functional impairment, inflammation, and elevated blood pressure. Also, BSO treatment increased the activity of phase II antioxidant enzyme, NAD(P)H: quinone oxidoreductase-1 (NQO-1). BSO and ML385 co-treatment exhibited a robust increase in blood pressure, oxidative stress and intensified the renal function deterioration as indicated by a significant increase in serum creatinine, urinary albumin excretion rate, and albumin to creatinine ratio and decreased glomerular filtration rate (GFR). Also, BSO and ML385 co-treatment downregulated NQO-1 and significantly altered the inflammatory cytokines, IL-1β and IL-10 levels. A D1R agonist SKF38393 failed to promote urinary sodium excretion indicating functional impairment in renal D1R. ML385 per se did not affect mean arterial pressure, GFR, and renal D1R function. Taken together, we concluded that the Nrf2 inhibition aggravated oxidative stress and inflammation by diminishing phase II antioxidant defense that deteriorates renal function and contributes to the development of hypertension in mice

Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on membrane enzymes, carbohydrate metabolism and oxidative damage in rat liver

Cisplatin (CP) is a potent anti-cancer drug widely used against solid tumors. However, it exhibits pronounced adverse effects including hepatotoxicity. Several strategies were attempted to prevent CP hepatotoxicity but were not found suitable for therapeutic application. Nigella sativa has been shown to prevent/reduce the progression of certain type of cardiovascular, kidney and liver diseases. Present study investigates whether N. sativa oil (NSO) can prevent CP induced hepatotoxic effects. Rats were divided into four groups viz. control, CP, NSO and CPNSO. Animals in CPNSO and NSO group were administered NSO (2 ml/kg bwt, orally) with or without single hepatotoxic dose of CP (6 mg/kg bwt, i.p.) respectively. CP hepatotoxicity was recorded by increased serum ALT and AST activities. CP treatment caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased enzymatic and non-enzymatic antioxidants. Furthermore, the activities of various carbohydrate metabolism and membrane enzymes were altered by CP treatment. In contrast, NSO administration to CP treated rats, markedly ameliorated the CP elicited deleterious alterations in liver. Histopathological observations showed extensive liver damage in CP treated animals while greatly reduced tissue injury in CPNSO group. In conclusion, NSO appears to protect CP induced hepatotoxicity by improving energy metabolism and strengthening antioxidant defense mechanism. Keywords: Cisplatin, Nigella sativa oil, Carbohydrate metabolism, Antioxidan

β-Cyclocitral: Emerging Bioactive Compound in Plants

β-cyclocitral (βCC), a main apocarotenoid of β-carotene, increases plants’ resistance against stresses. It has recently appeared as a novel bioactive composite in a variety of organisms from plants to animals. In plants, βCC marked as stress signals that accrue under adverse ecological conditions. βCC regulates nuclear gene expression through several signaling pathways, leading to stress tolerance. In this review, an attempt has been made to summarize the recent findings of the potential role of βCC. We emphasize the βCC biosynthesis, signaling, and involvement in the regulation of abiotic stresses. From this review, it is clear that discussing compound has great potential against abiotic stress tolerance and be used as photosynthetic rate enhancer. In conclusion, this review establishes a significant reference base for future research