Abstract
The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.
Highlights
The number of patients with diabetes has more than doubled in three decades, and is currently estimated to be nearly 350 million [1]
In contrast to the general view of BBR as a neuroprotective nutraceutical, we report that BBR causes neurotoxic effects on cultured cerebellar granule neurons (CGN) and hippocampal neurons (HCN)
Neurotoxicity of BBR was completely blocked by the NMDA receptor antagonists memantine and MK-801, with partial protection achieved with the mitochondrial permeability transition pore (PTP) inhibitor and perturbations in the respiratory chain [40,41,48]
Summary
The number of patients with diabetes has more than doubled in three decades, and is currently estimated to be nearly 350 million [1]. Management of hyperglycemia is a key intervention strategy in diabetes. In addition to lifestyle-directed interventions, a variety of oral pharmacological agents that improve insulin sensitivity are used to treat type 2 diabetes (T2D) and the prediabetic state [2]. The prevalence of age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), is on the rise, affecting more than 34 million people worldwide [3]. For AD, only symptomatic pharmacotherapies are available. In addition to the industrial drug development efforts for T2D, AD and their prodromal phases, complementary and alternative medicine treatments are actively being explored
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