Neuroprotection Comparison of Rosmarinic Acid and Carnosic Acid in Primary Cultures of Cerebellar Granule Neurons

Abstract

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.

Neuroprotective Effects of Methyl Caffeate against Hydrogen Peroxide-Induced Cell Damage: Involvement of Caspase 3 and Cathepsin D Inhibition

“…These results suggest involvement of inhibition of apoptotic and necrotic processes in the neuroprotective action of MC. It should be noted that previous studies demonstrated that CA or its derivatives inhibited apoptotic processes in neuronal cells which were induced by various factors (e.g., low potassium level, H 2 O 2 , serum deprivation) [ 5 , 8 , 13 , 19 , 40 ] and our present results extend these data by showing the effects of MC in the oxidative stress-based model. It is also in line with previous data from non-neuronal cells (kidney epithelium cell line LLC-PK) where MC (100 μM) reduced the contrast-induced caspase-3 activity and increased cell survival [ 54 ].…”

“…We rather think that when MC was given 30 min after H 2 O 2 , the cellular damage reached an advanced stage, at which MC was not protective any longer. It should be noted that most previous studies testing neuroprotective potential of CA derivatives usually used pre-treatment protocols (24 h, 2 h, or 1 h before toxin exposure) but without any comparisons between them [ 13 , 19 , 24 , 40 ]. The relatively narrow time window of MC efficacy (the best effects in pre-treatment group, slightly worsened in co-treatment group and lack of effect in post-treatment group) found in our study suggests that it might be mainly recommended for preventive strategy of neuronal damage, but not for reducing already existing brain injury, e.g., in the late phase of stroke.…”

“…In contrast to CA or its most often studied derivatives (CGA, CAPE, or rosmarinic acid) [ 16 , 18 , 19 ], no data on intracellular mechanisms involved in neuroprotection mediated by MC were available. Previously, we showed that the mechanisms of H 2 O 2 -induced cell damage involved activation of both caspase-3 and lysosomal protease, cathepsin D [ 41 , 42 ].…”

“…According to the literature published so far CA and its derivatives seem to be the most promising candidates for neuroprotective agents since they possess relatively higher antioxidant activity and are protective against a wider range of harmful factors when compared to other HCAs [ 8 , 10 , 12 , 13 ]. The representatives of this class of phenolic compounds most often studied so far in pre-clinical models of neurodegeneration include caffeic acid phenyl ester (CAPE, the main active component of propolis), chlorogenic acid (CGA, present in abundance in green coffee), chicoric acid, CA and rosmarinic acid (active component of rosemary herb) [ 14 , 15 , 16 , 17 , 18 , 19 ]. These compounds are characterized by pleiotropic mechanisms of action encompassing the activation of Nrf2/ARE/HO-1 pathway and induction of phase II enzymes (SOD, GSH, NADPH oxidase, xanthine oxidase), inhibition of calpains, attenuation of apoptotic and neuroinflammatory processes, inhibition of p38 and JNK pathways, induction of autophagy, activation of pro-survival PI3-K/Akt and MAPK/ERK1/2 pathways and stimulation of production of growth factors (NGF, BDNF, GDNF, VEGF) [ 5 , 6 , 7 , 15 , 18 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Melissa officinalis L. hydro‐alcoholic extract inhibits anxiety and depression through prevention of central oxidative stress and apoptosis

“…Besides, evidence shows that prolonged exposure to high concentrations of CORT can induce mitochondrial dysfunction and neuronal apoptosis (Gong, Zhang, Guo, & Fu, 2018; B. Liu et al., 2011; Woo et al., 2018). Additionally, the neuroprotective effect of RA, the main phytochemical content of MO, has been demonstrated in a large body of studies, and is mainly through suppression of oxidative stress and the apoptosis pathway (Cui et al., 2018; Khamse et al., 2018; H. J. Lee et al., 2008; Taram, Ignowski, Duval, & Linseman, 2018). It seems that both the increase in CORT and ROS overproduction could activate apoptotic signalling pathways, which might be ameliorated by MO through relieving the oxidative stress and CORT levels.…”