Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

Abstract

Rivastigmine is clinical drug for patients of Alzheimer’s disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Further the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

Rivastigmine ameliorates indomethacin experimentally induced gastric mucosal injury via activating α7nAChR with inhibiting oxidative stress and apoptosis

“…PCNA, proliferating cell nuclear antigen. et al [49] confirmed the present results as they found that RIVA has a significant ameliorative effect on AD's related biochemical alterations, protein degradation machinery, and neuronal apoptosis through the inhibitory effect of RIVA on AChE activity.…”

“…[ 8,38 ] RIVA decreased oxidative stress and apoptosis. [ 11,49 ] Therefore, RIVA increased the HO‐1 level. This may explain the increase in gastric HO‐1 levels in RIVA‐treated rats as observed in our study.…”

UBA52 is crucial in HSP90 ubiquitylation and neurodegenerative signaling during early phase of Parkinson’s disease

“…The experimental rats were anesthetized using a mixture of xylazine (10 mg/kg) and ketamine (80 mg/kg), mounted on the stereotaxic apparatus (Stoelting, USA) and a specific region was located by measuring coordinates from bregma(Anon n.d.). Unilateral administration (on the right side of rat brain) of rotenone (dissolved in 3μl DMSO, 6μg in each region) was given in the substantia nigra (SN) and striatum (STR) region (Gupta, et al 2021). Appropriate care of rats was taken to prevent mortality and after completion of experimental duration (3 days post administration) the rats were sacrificed, both SN and STR were isolated and processed for various assays or the brains were fixed for histological or immunofluorescence studies.…”

“…Proteasome activity was estimated in both cell (WT and Myc-UBA52) and tissue lysates as reported by us previously (Gupta, Tiwari, et al 2021) utilizing trypsin (Z-ARR-AMC) and chymotrypsin (SUC-LLVY-AMC) substrate (Enzo life sciences). Reaction mixtures were incubated for 60 minutes at 37 °C in dark and the fluorescence intensity was measured using fluorimeter (Varian Cary Eclipse, USA) at excitation/emission 360/460nm, respectively.…”

Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma

“…Three transmembrane ER sensors, including activating transcription factor 6 (ATF6), protein kinase R-(PKR-) like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 (IRE1α), have been found to determine the triggering of ER stress and subsequent activation of the UPR [7]. With the increasing recognition of ER stress mechanisms, ER stress dysregulation has been found to play an essential role in various human diseases, including cardiometabolic diseases [8][9][10], diabetes [11,12], chronic kidney disease [13,14], Alzheimer's disease [15,16], and cancers [17][18][19][20]. Chronic activation of the UPR caused by ER stress, viral infection, or hepatic obesity may lead to liver dysfunction and disturbances in lipid and glucose metabolism [21].…”