Role of Nitric Oxide, TNF-α and Caspase-3 in Lead Acetate-Exposed Rats Pretreated with Aqueous Rosmarinus officinalis Leaf Extract.

Lead (Pb) toxicity is a worldwide significant public health challenge causing several neurological disorders. Reports indicate that plants rich in antioxidants, such as Rosmarinus officinalis (RO), can counteract Pb accumulation and its toxicity in the brain. Due to a dearth of literature evidence demonstrating the protective activity of RO against Pb toxicity, this study investigated such activity in Wistar rats. Thirty-six Wistar rats were allocated into six groups (n=6), namely I (control), II (lead acetate [Pb]; 100 mg/kg b.w.), III (100 mg/kg of RO and 100 mg/kg of Pb), IV (200 mg/kg of RO and 100 mg/kg of Pb), V (100 mg/kg b.w. of RO) and VI (200 mg/kg b.w. of RO). After 28 days, neurobehavioural, antioxidant, lipid peroxidation, apoptotic and inflammatory activities as well as the histology of the cerebellum were evaluated. Body weight, locomotion and exploration as well as antioxidant enzymes were significantly (p < 0.05) decreased in Pb-exposed rats when compared to control. Conversely, lipid peroxidation, nitric oxide, tumour necrosis factor-alpha and caspase-3 activities were significantly (p < 0.05) upregulated in the Pb-exposed rats when compared to control. These parameters were, however, significantly (p<0.05) attenuated in the RO-pretreated rats when compared to Pb-exposed rats. Cerebellar histology of the Pb-exposed rats showed severe degeneration of the Purkinje cells whereas the RO-pretreated rats showed better cerebellar architecture. These findings demonstrate that the neuroprotective activity of RO is facilitated via its effective antioxidant, anti-inflammatory and anti-apoptotic effects.

Inhibition of γH2AX, COX-2 and regulation of antioxidant enzymes in MPP+-exposed SH-SY5Y cells pre-treated with rutin.

Many plant-derived bioactive compounds such as rutin are reportedly effective in attenuating neuronal death in most neurodegenerative disorders. Parkinson's disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra of the midbrain, and has previously been modelled in-vitro through the specific neurotoxic activity of 1-methyl-4-phenylpyridinium (MPP+) on dopaminergic neurons. Rutin is a bioflavonoid with multiple pharmacological effects, and this study investigated the neuroprotective effects of rutin in the human dopaminergic SH-SY5Y cell line using the neurotoxin MPP+. SH-SY5Y cells pretreated with rutin, were exposed to MPP+ and evaluated for cell viability, nitric oxide (NO), reactive oxygen species (ROS) and antioxidant enzymes activities. In addition, western blot techniques were used to determine the protein expression levels of γH2AX and COX-2. Rutin significantly attenuated MPP+-induced loss of cell viability, mitigated ROS and NO production and inhibited the disruption of antioxidant enzymes activity. It was also observed that rutin significantly reduced protein expression levels of γH2AX and COX-2 in SH-SY5Y cells treated with MPP+. Taken together, findings from this study tend to suggest that rutin is a promising neuroprotective compound for the treatment of PD through its effects on some of the mechanisms that characterize this neurodegenerative disease.

The Developing Cerebellum as a Target for Toxic Substances: Protective Role of Antioxidants.

Cerebellar development begins during the late embryological period and continues to undergo organizational changes long after birth. The cerebellum is particularly susceptible to developmental abnormalities on exposure to oxidants and free radicals, thus leading to oxidative stress. Oxidative stress occurs when there is an imbalance between reactive oxygen species generation and antioxidant defences which may disrupt signalling pathways, leading to cerebellar anomalies and dysfunction. In this regard, this review assesses current research underlining the importance of the cerebellum, provides an update on substances affecting cerebellar development and highlights some promising antioxidants that may play a role in attenuating toxicity in the developing cerebellum. To accomplish this, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system was employed and key scientific databases such as Science Direct, PubMed, Scopus, Web of Science and Google Scholar were searched to explore and collect information on the cerebellum and the role of antioxidants during its development. Originally, 109 articles were obtained but 22 articles which met the inclusion criteria were selected for the review. These findings provide an updated compilation of antioxidants capable of attenuating oxidative damage in the developing cerebellum, thus allowing future interdisciplinary studies in the form of clinical applications for screening and possible development of novel therapeutic agents from the identified products.

Regulation of AKT/AMPK signaling, autophagy and mitigation of apoptosis in Rutin-pretreated SH-SY5Y cells exposed to MPP.

Accumulating evidence suggest that apoptosis, autophagy and dysregulation of signaling pathways are common mechanisms involved in Parkinson's disease (PD) pathogenesis, and thus development of therapeutic agents targeting these mechanisms may be useful for the treatment of this disease. Although rutin (a bioflavonoid) is reported to have pharmacological benefits such as antioxidant, anti-inflammatory and antitumor activities, there are very few reports on the activity of this compound in 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Accordingly, we investigated the effects of rutin on apoptosis, autophagy and cell signaling markers (AKT/AMPK) in SH-SY5Y cells exposed to MPP+. Results show reduced changes in nuclear morphology and mitigation of caspase 3/7 and 9 activities in rutin pre-treated cells exposed to MPP+. Likewise, rutin regulated cell signaling pathways (AKT/AMPK) and significantly decreased protein expression levels of cleaved PARP, cytochrome c, LC3-II and p62. Also, rutin significantly increased protein expression levels of full-length caspase 3 in SH-SY5Y cells treated with MPP+. Transmission electron microscope (TEM) images demonstrated a reduction in autophagosomes in rutin-pretreated SH-SY5Y cells exposed to MPP+. These results provide experimental support for rutin's neuroprotective activity against MPP+-induced toxicity in SH-SY5Y cells, which is as a promising therapeutic agent for clinical trials in humans.

Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin.

Parkinson's disease (PD) is a common neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years. While treatment options for PD are limited, reports show that plant-derived bioactive compounds such as rutin possess numerous pharmacological benefits, including antioxidant and antiapoptotic activities. This study aimed to investigate the potential role of rutin in MPP+-treated SH-SY5Y neuroblastoma cells, an established cell model of PD. Our findings reveal increased concentrations of Ca2+ and endoplasmic reticulum (ER) stress as well as impaired mitochondrial membrane potential and bioenergetic status in SH-SY5Y cells treated with MPP+ only. This is demonstrated by a significant reduction in the expression levels of BiP, significantly reduced basal respiration, maximal respiration, and spare respiratory capacity as well as a significant increase in the expression levels of CHOP; however, these effects were significantly attenuated following pretreatment with rutin. Also, rutin significantly improved basal and compensatory glycolysis as a response to an impaired oxidative phosphorylation system triggered by MPP+, characterized by deficient ATP production. In conclusion, our findings provide the first evidence on the ability of rutin to maintain Ca2+ homeostasis, inhibit ER stress, and protect the mitochondria in MPP+-treated SH-SY5Y cells.

GRP78/BIP/HSPA5 as a Therapeutic Target in Models of Parkinson's Disease: A Mini Review.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopamine neurons in the substantia nigra pars compacta of the midbrain. Reports from postmortem studies in the human PD brain, and experimental PD models reveal that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of PD. In times of stress, the unfolded or misfolded proteins overload the folding capacity of the ER to induce a condition generally known as ER stress. During ER stress, cells activate the unfolded protein response (UPR) to handle increasing amounts of abnormal proteins, and recent evidence has demonstrated the activation of the ER chaperone GRP78/BiP (78 kDa glucose-regulated protein/binding immunoglobulin protein), which is important for proper folding of newly synthesized and partly folded proteins to maintain protein homeostasis. Although the activation of this protein is essential for the initiation of the UPR in PD, there are inconsistent reports on its expression in various PD models. Consequently, this review article aims to summarize current knowledge on neuroprotective agents targeting the expression of GRP78/BiP in the regulation of ER stress in experimental PD models.

Rutin as a Potent Antioxidant: Implications for Neurodegenerative Disorders.

A wide range of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases, share common mechanisms such as neuronal loss, apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation. Intervention strategies using plant-derived bioactive compounds have been offered as a form of treatment for these debilitating conditions, as there are currently no remedies to prevent, reverse, or halt the progression of neuronal loss. Rutin, a glycoside of the flavonoid quercetin, is found in many plants and fruits, especially buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges. Pharmacological studies have reported the beneficial effects of rutin in many disease conditions, and its therapeutic potential in several models of NDs has created considerable excitement. Here, we have summarized the current knowledge on the neuroprotective mechanisms of rutin in various experimental models of NDs. The mechanisms of action reviewed in this article include reduction of proinflammatory cytokines, improved antioxidant enzyme activities, activation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the activities of mitochondrial complex enzymes. Taken together, these findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.