Abstract
The aberrant generation of oxygen and nitrogen free radicals can cause severe damage to key cellular components, resulting in cell apoptosis. Similarly, excitotoxicity leads to protease activation and mitochondrial dysfunction, which subsequently causes cell death. Each of these factors play critical roles in the neuronal cell death underlying various neurodegenerative diseases. Procyanidin B2 (PB2) is a naturally occurring polyphenolic compound found in high concentrations in cocoa, apples, and grapes. Here, we examine the neuroprotective effects of PB2 in primary cultures of rat cerebellar granule neurons (CGNs) exposed to various stressors. CGNs were pre-incubated with PB2 and then neuronal stress was induced as described below. Mitochondrial oxidative stress was triggered with HA14-1, an inhibitor of the pro-survival Bcl-2 protein which induces glutathione-sensitive apoptosis. Glutamate and glycine were used to induce excitotoxicity. Sodium nitroprusside, a nitric oxide generating compound, was used to induce nitrosative stress. We observed significant dose-dependent protection of CGNs with PB2 for all of the above insults, with the greatest neuroprotective effect being observed under conditions of nitrosative stress. Intriguingly, the neuroprotective effect of PB2 against nitric oxide was superoxide-dependent, as we have recently shown for other catechol antioxidants. Finally, we induced neuronal stress through the removal of depolarizing extracellular potassium and serum (5K conditions), which is a classical model of intrinsic apoptosis in CGNs. PB2 did not display any significant protection against 5K-induced apoptosis at any concentration tested. We conclude that PB2 offers neuronal protection principally as an antioxidant by scavenging reactive oxygen and nitrogen species instead of through modulation of pro-survival cell signaling pathways. These findings suggest that PB2 may be an effective neuroprotective agent for the treatment of neurodegenerative disorders.
Highlights
Neurodegeneration in critical areas of the brain and spinal cord leads to various diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)
We first examined the possible protective effects of Procyanidin B2 (PB2) against apoptosis induced by removing depolarizing potassium (5K)
These results indicate that PB2 has a high propensity to protect neuronal damage caused by nitric oxide (Figure 6B)
Summary
Neurodegeneration in critical areas of the brain and spinal cord leads to various diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). This process results in the leakage of electrons to molecular oxygen, forming the reactive species, superoxide, which can dismutate to form hydrogen peroxide (H2 O2 ) and subsequently hydroxyl radicals [5] These ROS can cause damage to mitochondrial components and initiate degradative processes by overwhelming the ability of the cell to enzymatically remove oxidatively damaged products [6]. Glutathione (GSH), an essential endogenous antioxidant, has been found to be depleted in several neurodegenerative conditions [9,10,11] This depletion prevents the cell from being able to scavenge reactive free radical species, which target cellular components such as those found in mitochondria, resulting in more severe ROS production and increased oxidative stress.
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