Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AβO. Naturally-derived compounds have been proposed as potential modifiers of Aβ-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AβO. We examined the protective effect of boldine (1–10 μM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AβO (24–48 h). We found that boldine interacts with Aβ in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AβO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AβO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AβO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aβ and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aβ in vivo.

Boldine Alkaloid: Holistic Overview on Potential Health Benefits and Medicinal Merits a comprehensive review

“…Additionally, it restored variations in intracellular Ca 2+ levels linked to mitochondria or the endoplasmic reticulum in HT22 cells that had received AbO treatment. It reversed the AbO-induced decrease in mitochondrial respiration in HT22 hippocampus cells, fully recovered the decline in mitochondrial membrane potential, and decreased the rise in mitochondrial reactive oxygen species [50].…”

“…While long-term oral administration of boldine in AD mice revealed preventing the increase in glial hemichannel activity, astrocytic Ca +2 signal, ATP, glutamate release, and alleviated hippocampal neuronal suffering. Another study was performed to investigate the neuroprotective effect of boldine in cellular models (primary hippocampal neurons and HT22 hippocampal derived cell line treated with amyloid beta peptide (Ab) oligomers) of Alzheimer's disease [50]. Results showed that boldine interacts with Ab in silico, preventing its aggregation and defending hippocampus neurons against synaptic failure brought on by AbO.…”

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome

“…In addition, boldine attenuates the AβO-induced decrease in mitochondrial membrane potential and mitochondrial respiration as well as the increase in mitochondrial ROS in HT22 hippocampal cells. Therefore, boldine exhibits neuroprotection in an AD model by both direct interaction with Aβ and prevention of mitochondrial dysfunction [ 67 ]. Moreover, boldine can improve the learning and memory of Swiss albino male young and aged mice, possibly by suppressing brain acetylcholinesterase activity and oxidative stress [ 68 ].…”

Free radical biology in neurological manifestations: mechanisms to therapeutics interventions

“…Neurotoxins such as Aβ, epoxide hydrolase (sEH), dichloroacetic acid, paroxetine, NO, and doxorubicin increase the FR concentration, which is responsible for ROS-induced neuronal cell death and ultimately leads to cognitive impairment and synaptic dysfunction. Administration of neurotoxins disrupts the mitochondrial membrane permeability and alters the calcium homeostasis (Toledo et al 2021;Sheikholeslami et al 2021;Wang et al 2021;Wu et al 2021;Wei et al 2021). To reverse the effects of neurotoxin-induced oxidative stress, the efficacy of antioxidant properties has been tested in both in vivo and in vitro conditions.…”