A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or ...neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic. All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.
A key molecular mechanism that contributes to secondary injury after TBI is free radical damage which is induced by the aberrant production of reactive oxygen species (ROS) and reactive nitrogen ...species (RNS). The limiting precursor for GSH synthesis is the amino acid cysteine. ...agents which augment the available cysteine pool act as GSH precursors and could be used to enhance GSH synthesis making the brain more resilient to TBI (preventative) or improving recovery post-TBI (restorative). Administration of a single dose of NAC post-TBI significantly decreased malondialdehyde levels (an index of lipid peroxidation), increased superoxide dismutase and GPx levels, and protected neurons when compared to untreated rats that received TBI (Hicdonmez et al., 2006). When GSNO was administered to rats 2 hours after a controlled cortical impact TBI, the integrity of the blood brain barrier was preserved, apoptosis was reduced, and macrophages showed reduced inducible nitric oxide synthase expression when compared to vehicle-treated injured animals.
Rho family GTPases (eg., RhoA, Rac1 and Cdc42) are monomeric G-proteins that act as key transducers of extracellular signals to the actin cytoskeleton. In the nervous system, Rho family GTPases are ...essential regulators of neuronal growth cone motility, axonal migration, and dendritic spine morphogenesis. Given these vital functions, it is perhaps not surprising that mutations in several proteins involved in Rho GTPase signaling are causative in some forms of mental retardation. In addition, numerous recent studies have identified Rho family GTPases as central players in the molecular pathways that determine neuronal survival and death. Interestingly, individual Rho family members have been shown to play either a pro-death or pro-survival role in the nervous system depending on both the type of neuron and the particular neurodegenerative insult involved. This review summarizes current work demonstrating a critical role for Rho family GTPases and their effectors in the regulation of neuronal development, survival, and death. These findings may be particularly relevant in the context of specific neurodegenerative disorders in which Rho family GTPase function is altered, such as loss-of-function of the Rac1 guanine nucleotide exchange factor, alsin, in juvenile-onset amyotrophic lateral sclerosis.
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 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.
The COVID-19 pandemic affects more than 81 million people worldwide with over 1.7 million deaths. As the population returns to work, it is critical to develop tests that reliably detect ...SARS-CoV-2-specific antibodies. Here we present results from a multiplex serology test for assessing the antibody responses to COVID-19. In an initial large cohort, this test shows greater than 99% agreement with COVID-19 PCR test. In a second outpatient cohort consisting of adults and children in Colorado, the IgG responses are more robust in positive/symptomatic participants than in positive/asymptomatic participants, the IgM responses in symptomatic participants are transient and largely fall below the detection limit 30 days after symptom onset, and the levels of IgA against SARS-CoV-2 receptor binding domain are significantly increased in participants with moderate-to-severe symptoms compared to those with mild-to-moderate symptoms or asymptomatic individuals. Our results thus provide insight into serology profiling and the immune response to COVID-19.
Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current ...study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.
•The role of Rac and Rho in the regulation of motor neuron survival is unclear.•Inhibition of Rac or activation of Rho induces motor neuron cell death in vitro.•Active Rac1 is decreased in spinal motor neurons of G93A mutant hSOD1 mice.•RhoB redistributes from motor neuron soma to their axons in end-stage mice.•An imbalance between Rac and Rho signaling may underlie the pathogenesis of ALS.
Anthocyanins are being increasingly investigated for their neuroprotective and antineuroinflammatory effects; however, the overall bioavailability of many anthocyanins is relatively low. In contrast, ...phenolic acids, metabolites of many polyphenols, including anthocyanins, have been shown to accumulate in tissue at higher concentrations than those of parent compounds, suggesting that these metabolites may be the bioactive components of anthocyanin-rich diets. We examined the neuroprotective capacity of two common phenolic acids, 4-hydroxybenzoic acid (HBA) and protocatechuic acid (PCA), in primary cultures of cerebellar granule neurons. Both HBA and PCA are capable of mitigating oxidative stress induced by hydrogen peroxide, which is thought to contribute to neuronal cell death in neurodegeneration. Under conditions of nitrosative stress, which occur during inflammation in the central nervous system, only PCA was neuroprotective, despite similar structural characteristics between HBA and PCA. Intriguingly, this trend was reversed under conditions of excitotoxicity, in which only HBA was neuroprotective. Lastly, we explored the anti-inflammatory activity of these compounds in microglial cells stimulated with lipopolysaccharide. PCA was an effective anti-inflammatory agent, reducing nitric oxide production, while HBA had no effect. These data indicate that phenolic acids possess distinct neuroprotective and anti-inflammatory characteristics that could make them suitable for the treatment of neurodegeneration.
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