Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, are characterized by the progressive loss of neurons in specific regions of the ...brain and/or spinal cord. Neuronal cell loss typically occurs by either apoptotic or necrotic mechanisms. Oxidative stress and nitrosative stress, along with excitotoxicity and caspase activation, have all been implicated as major underlying causes of neuronal cell death. Diverse nutraceuticals (bioactive compounds found in common foods) have been shown to have neuroprotective effects in a variety of in vitro and in vivo disease models. In the current study, we compared the neuroprotective effects of two polyphenolic compounds, rosmarinic acid and carnosic acid, which are both found at substantial concentrations in the herb rosemary. The capacity of these compounds to rescue primary cultures of rat cerebellar granule neurons (CGNs) from a variety of stressors was investigated. Both polyphenols significantly reduced CGN death induced by the nitric oxide donor, sodium nitroprusside (nitrosative stress). Rosmarinic acid uniquely protected CGNs from glutamate-induced excitotoxicity, while only carnosic acid rescued CGNs from caspase-dependent apoptosis induced by removal of depolarizing extracellular potassium (5K apoptotic condition). Finally, we found that carnosic acid protects CGNs from 5K-induced apoptosis by activating a phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The shared and unique neuroprotective effects of these two compounds against diverse modes of neuronal cell death suggest that future preclinical studies should explore the potential complementary effects of these rosemary polyphenols on neurodegenerative disease progression.
Abstract While the number of patients diagnosed with neurodegenerative disorders like Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease is increasing, there are currently no ...effective treatments that significantly limit the neuronal cell death underlying these diseases. Chlorogenic acid (CGA)1 , a polyphenolic compound found in high concentration in coffee, is known to possess antioxidant and free radical scavenging activity. In this study, we investigated the neuroprotective effects of CGA and its major metabolites in primary cultures of rat cerebellar granule neurons. We show that CGA and caffeic acid displayed a dramatic protective effect against the nitric oxide donor, sodium nitroprusside. In marked contrast, ferulic acid and quinic acid had no protective effect against this nitrosative stress. While CGA and quinic acid had no protective effect against glutamate-induced cell death, caffeic acid and ferulic acid significantly protected neurons from excitotoxicity. Finally, caffeic acid was the only compound to display significant protective activity against hydrogen peroxide, proteasome inhibition, caspase-dependent intrinsic apoptosis, and endoplasmic reticulum stress. These results indicate that caffeic acid displays a much broader profile of neuroprotection against a diverse range of stressors than its parent polyphenol, CGA, or the other major metabolites, ferulic acid and quinic acid. We conclude that caffeic acid is a promising candidate for testing in pre-clinical models of neurodegeneration.
Neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), include the progressive loss of structure and function of neurons leading ...to neuronal death. All of these diseases are fatal, as there is no cure for them. The causes of these diseases are unknown; however, there are many proposed mechanisms that lead to neurodegenerative diseases. Oxidative stress is the leading cause of cell death in neurodegenerative diseases, in addition to other mechanisms including endoplasmic reticulum stress, proteasome inhibition, nitrosative stress, inflammation and excitotoxicity. More understanding of the death mechanisms at work in neurodegeneration is necessary to find ways to block those mechanisms in order to slow or stop the progress of these disorders. Interest in nutraceutical compounds has increased recently because of the discovery their bioactive properties. Many studies have suggested that nutraceutical compounds have the ability to inhibit the different death pathways. In this study, we investigated the neuroprotective efficacy of seven natural compounds in several in vitro models of cell death. In primary cultured rat cerebellar granule neurons (CGNs), pre-incubation with caffeic acid, which is abundant in green coffee beans, completely protected against cell death induced by several mechanisms. Caffeic acid protected against effects of sodium nitroprusside (SNP), an agent that induces nitrosative stress, glutamate /glycine which prompts excitotoxicity, hydrogen peroxide, an inducer of oxidative stress, proteasome inhibitors, 5K medium that induces caspase-dependent apoptosis, and endoplasmic reticulum stressors. Furthermore, caffeic acid reduced inflammation induced by lipopolysaccharides in BV2 mouse microglial cell line. Chlorogenic acid and ferulic acid protected from one agent. Chlorogenic acid only protected CGNs from SNP; however, ferulic acid protected the CGNs from glutamate toxicity. Quinic acid did not protect from any agents or stressors. Rosmarinic acid protected the CGNs against glutamate toxicity, and carnosic acid protected the cells from 5K medium that typically induces apoptosis. Both rosmarinic acid and carnosic acid protected the cells from SNP and subsequent nitrosative stress. We further suggest that carnosic acid protects CGNs from caspase-dependent apoptosis through activation of the phosphoinositide 3-kinase (PI3K) pro-survival pathway. Pyrroloquinoline quinone (PQQ) also showed a significant protection against oxidative stress typically induced by hydrogen peroxide and copper chloride. The cumulative data suggest that nutraceutical compounds hold promising therapeutic implications for neurodegenerative disease.
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