Neuroprotective Effects of S-allyl cysteine(SAC)
S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) has been used in several works in order to find effective, therapeutic, and preventive strategies for intervention in neurodegenerative diseases.
6.1. Neurotrophic Effect of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract)
Moriguchi et al. reported the positive actions of garlic compounds (including SAC) with a thioallyl group in rat hippocampal neurons culture. In this work, S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) increased survival and axonal branching from neurons. Based on these findings, this group suggested that thioallyl group is essential for neurotrophic activity [91]. These data suggest that S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) is a compound that not only acts as an antioxidant agent but also as a neurotrophic molecule.
6.2. S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in Experimental Models of Alzheimer’s Disease (AD)
AD is a devastating neurodegenerative disorder which causes progressive loss of cognitive abilities, the accumulation of Aβ deposits in the basal forebrain, hippocampus, and cortex, together with oxidative stress, have been consistently implicated in the pathogenesis of this disorder [92]. In this regard, the design of a treatment with antioxidant and/or antiamyloidogenic properties represents an approach of considerable therapeutic value for the prevention of the disease progression.
The effect of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) on PC12 cells exposed to has also been evaluated. SAC suppressed the generation of ROS; attenuated caspase-3 activation, DNA fragmentation, and PARP cleavage eventually protecting against Aβ-induced cell death [93, 94]. Moreover, S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) attenuated cell death induced by Aβ in organotypic hippocampal culture and cultured hippocampal neurons in a concentration-dependent manner, an effect apparently mediated by the caspase-12-dependent pathway [95–97].
On the other hand, some studies have shown that AD patients exhibit an overstimulation of the N-methyl-D-aspartate receptor in some time points of the disease progress [98]. In order to reproduce this state, Aβ and ibotenic acid (a potent N-methyl-D-aspartate agonist) administrations have been used in organotypic hippocampal cultures resulting in a time-dependent neuronal damage, a feature that SAC administration (10 and 100 mM) significantly attenuated in the CA3 area [95].
AD involves misfolding and aggregation of proteins which increased endoplasmic reticulum stress [99]. Tunicamycin, an inhibitor of N-glycosylation in endoplasmic reticulum, reproduces some severe neurological alterations in animals (resembling neurological disorders) through the induction of endoplasmic reticulum stress. The role of SAC (10−8–10−5 M) on tunicamycin-mediated cell death was investigated in PC12 cells and hippocampal neurons, showing a selective neuroprotective effect on the caspase-12-dependent apoptotic pathway [96, 100]. In another work, Aβ plus tunicamycin-induced neurotoxicity was assessed in organotypic hippocampal slice cultures, where SAC (100 μM) improved cell viability in area CA3 and dentate gyrus. Simultaneously, SAC reversed calpain activity as well as the active forms of caspase-12 and caspase-3, without changing the increased levels of endoplasmic reticulum chaperones (GRP94 and −78) or C/EBP homologous protein. The authors suggest that SAC could either directly interact with calpain or alter the environment in the vicinity of the endoplasmic reticulum lumen without affecting unfolded protein responses or the C/EBP homologous protein-mediated signaling pathway induced by Aβ plus tunicamycin [101].
In addition, the protective effect of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in Aβ toxicity could not be only related to its antioxidant activity as Gupta and Rao investigated the effect of SAC on Aβ aggregation in vitro. SAC (10–50 M) not only inhibited Aβ fibrillation in a dose-dependent manner and disestablished preformed Aβ-peptide fibrils, but also bound to Aβ fibrils. In a docking protocol, the site suitable for accommodating SAC was identified around the Aβ40 structure. It was mentioned that S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) could interact with the positively charged Gln15-Lys16 segment. In fact, binding could be induced either by hydrophobic interactions between allyl chain and hydrophobic regions of Aβ (Phe 19 and Val 12), or by the H-bond between the -OH group of the carboxylic group of SAC and donator/acceptor groups of Aβ [102].
Since there is a possibility that AD results from inheritance of an autosomal dominant mutation in the amyloid precursor protein, the introduction of mutant amyloid precursor protein genes into suitable mouse pronuclei is used to build transgenic mouse models of AD. These mutant amyloid precursor protein transgenic models exhibit the progressive Aβ neuritic plaques formation, dystrophic neuritis, and neuroinflammation [103]. Interestingly, the dietary administration of SAC (20 mg/kg for 4 month) in one of these transgenic models decreased Aβ load, IL-1β reactive plaque-associated microglia, Tau2 reactivity, and GSK-3β protein, showing an antiamyloidogenic, anti-inflammatory, and antitangle activity (via GSK-3 β) [90].
Intracerebroventricular injection of streptozotocin to mice impairs brain biochemistry, cerebral glucose, energy metabolism, cholinergic transmission, and increases generation of free radicals, further leading to cognitive deficits; these effects are similar to sporadic dementia in humans. Pretreatment with SAC (30 mg/kg every day for 15 days) in intracerebroventricular streptozotocin-infused mice ameliorated hippocampal neuronal abnormalities, prevented the cognitive and neurobehavioral impairments, restored levels of reduced glutathione and its dependent enzymes (glutathione peroxidase and glutathione reductase), diminished lipid peroxidation, DNA fragmentation, and p53 levels, and increased Bcl2 levels [104].
Finally, SAC (1 g/L for 15 weeks, added to the drinking water) was tested in D-galactose-injected mice. D-Galactose induces AD-like pathological changes in the brain, including increased reactive oxygen species, decreased antioxidant enzyme activity, and enhanced Aβ-peptide expression. S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) decreased the brain levels of and , lowered amyloid precursor protein level and BACE1 expressions and activities (both of them being factors responsible for Aβ accumulation and AD progression), retained PKC activity and expression of PKC-α and PKC-γ, lowered Aβ accumulation, reduced the levels of advanced glycation end products (carboxymethyllysine, pentosidine), lowered aldose reductase activity and expression (an enzyme that facilitates the production of sorbitol and fructose, which in turn promote advanced glycation end products formation and glycative stress), and displayed antioxidant protection (evidenced by increased reduced glutathione content and glutathione peroxidase, superoxide dismutase, and catalase activities, accompanied by decreased levels of malondialdehyde, reactive oxygen species, and protein carbonyls) [105].
The aforementioned evidence serves to suggest that S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) might prevent the progression of AD by multiple mechanisms: antioxidant, antiamyloidogenic, anti-inflammatory, antitangle, and antiglycative activities (Figure 6). However, further studies are essential to determine if SAC is capable of displaying all these proprieties in humans.
<Portal: Garlife™-Garlic Extract>
6.3. S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in Ischemic Brain Damage
The effect of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in ischemic brain damage was tested at 100, 300, and 600 mg/kg i.p. applied 30 min prior the onset of ischemia in rats. SAC (300 mg/Kg) induced significant reduction of the infarct volume, water content, oxidative stress and improvement in motor performance and memory impairment [23, 80]. Moreover, in a two-vessel occlusion model in gerbils, the oral and i.p. administration of SAC 300 mg/kg increased the number of surviving cells/mm2 of CA1 region [106].
Hypertension is recognized as the most important risk factor for the development of ischemic cerebral infarction in humans [107]. Kim et al. evaluated the effect of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in stroke-prone spontaneously hypertensive rats, demonstrating that SAC (5%, 28 day of diet period) reduced mortality and the overall stroke-related behavioral score [108]. In another work, the same authors showed that SAC (300 mg/Kg) reduced the size of infarct area after 2 h occlusion and 22 h reperfusion, prevented neuronal cell death in CA1 region and inhibited the activity of ERK induced by focal ischemia in a middle cerebral artery occlusion model in gerbils, while in vitro exerted scavenging activity on peroxynitrite [28].
Additionally, it has been reported that the positive actions of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) seen in the cerebral ischemia-induced damage to the hippocampus may be due to the possible modulation of mitochondrial dysfunctions. SAC 300 mg/kg i.p. administered twice (15 min preocclusion and 2 h postocclusion at the time of reperfusion) in the middle cerebral artery occlusion model in rats, produced a significant decrease in mitochondrial lipid peroxidation, protein carbonyl levels, cytochrome c release, and intracellular H2O2 levels. Furthermore, S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) also restored the status of mitochondrial glutathione and glucose 6-phosphate dehydrogenase, ATP content, and the activity of mitochondrial respiratory complexes (I-IV) [109]. In conclusion, the protective effects of S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) on brain ischemic damage may be associated with the decrease of oxidative stress and the modulation of mitochondrial dysfunctions.
6.4. S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in Experimental Models of Huntington’s Disease
Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by the gradual and progressive loss of neurons, predominantly in the striatum. It is caused by a mutation in the huntingtin gen. Its main clinical manifestations are chorea, cognitive impairment, and psychiatric disorders, most of them related to striatal and cortical atrophy. Nowadays, there is no treatment to prevent or reduce the morphological and functional alterations seen in the brains of Huntington’s patients. For this reason, it is imperative to look for pharmacological strategies to improve the quality of life of these patients [110].
S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) has been used in two animal models of Huntington’s disease: 3-nitropropionic acid and quinolinic acid. SAC (300 mg/kg i.p.) administration to rats infused with 3-nitropropionic acid prevented behavioral alterations, increased manganese and copper/zinc superoxide dismutase activities, and decreased lipid peroxidation and mitochondrial dysfunction [111]. Simultaneously, SAC (0.75 mM) also decreased lipid peroxidation and mitochondrial dysfunction induced by 3-nitropropionic acid in synaptosomal fractions [112].
On the other hand, it has been reported that S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) bonds Fe2+ and Fe3+, preventing the redox cycling of iron, and consequently, the quinolinic acid induced-lipid peroxidation [70]. Alternatively, the effect of SAC was evaluated in a combined model of excitotoxicity/energy deficit produced by the coadministration of quinolinate and 3-nitropropionate acid in brain synaptosomal membranes. SAC abolished the quinolinic acid plus 3-nitropropionate acid-induced lipid peroxidation [113, 114]. The protective effect of SAC in these models has been attributed to its ability to preserve the cell redox status through its antioxidant properties and probably to its iron-binding properties.
6.5. S-Allyl cysteine (SAC, black garlic extract, aged garlic extract) in Experimental Models of Parkinson’s Disease
Parkinson’s disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, with the concomitant formation of intraneuronal fibrillar inclusions (Lewy bodies) and depletion of noradrenaline and serotonin in other brain stem nuclei. In addition, it shows oxidative tissue damage and bioenergetic deficits [115].
1-Methyl-4-phenylpyridinium (MPP+) is the stable metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and it causes nigrostriatal dopaminergic neurotoxicity, which in turn has been the most widely used model of Parkinson’s disease. Rojas et al. reported the neuroprotective effects of SAC against the oxidative stress induced by MPP+ in the mouse striatum. They found that SAC protected dopamine levels, improved hypolocomotion, decreased ROS production and lipid peroxidation, and increased Cu,Zn superoxide dismutase activity in mice injected with MPP+ [116]. Another Parkins
———————–
The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection. Ana L. Colín-González,1 Ricardo A. Santana,1 Carlos A. Silva-Islas,1 Maria E. Chánez-Cárdenas,1 Abel Santamaría,2 and Perla D. Maldonado
