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.

A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the 1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with and portraying IC values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound was the most potent multifunctional agent showing better inhibitory activity than ladostigil on all enzymes tested (hMAO-A IC = 4.31 μM, hMAO-B IC = 2.62 μM, eeAChE IC = 3.70 μM, eqBuChE IC = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound to be more stable than its diethyl-carbamate containing counterpart compound. Compound also exerted significant neuroprotection (52.62% at 1 μM) against MPP insult to SH-SY5Y neural cells and has good predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties and the potent neuroprotective ability of compound make it a promising compound for further development.

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.

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An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 µM concentration. This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC99 values of 8.31 -29.70 µM and 44.15 -57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively. These compounds were found to bind to albumin which may explain the variations in MIC between the two assays. Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria. Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect. Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria. Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.

Histological studies of the effects of oral administration of aqueous extract of Phyllanthus amarus commonly used in ethno medical practice in Africa for the management of various ailments such as kidney stones, dysentery, jaundice, diarrhoea and urogenital diseases on the kidney of adult Wistar rats were carefully studied. Rats of both sexes (n=24), average weight of 260g were randomly assigned into three groups: A, B and C of (n=8) in each group. Group A and B served as treatment groups (n=16) while group C (n=8) served as the control. The rats in the treatment groups (A & B) received 500mg/kg and 1000mg/kg body weight respectively of aqueous extract of Phyllanthus amarus orally through orogastric tube for twenty-eight days, while the control rats received equal volume of distilled water without the extract of Phyllanthus amarus added for the same period. The rats were fed with growers' mash purchased from Edo feeds and Flour Mill Ltd, Ewu, Edo state and were given water liberally. The rats were sacrificed on day twenty-nine of the experiment. The kidneys were carefully dissected out and quickly fixed in 10% formal saline for routine histological study after H&E method. The histological findings indicated that the treated sections of the kidneys showed hypertrophy of blood vessels, mild-severe infiltrate of chronic inflammatory cells and varying degrees of tubular necrosis when compared to the control sections. The findings indicated that the administration of Phyllanthus amarus extract has some adverse effects on the kidneys of adult Wistar rats. It is recommended that further studies aimed at corroborating these observations be carried out.

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