3.2. Garlic Compounds as Treatment for Ischemic Stroke
Compounds derived from garlic are known to have antioxidant and anti-inflammatory properties. They can scavenge different ROS
[53][54][76,77], and some (SAC, DATS, and DADS) show the ability to promote the activation of Nrf2 transcription factor, increasing endogenous antioxidant defense
[55][56][57][58][51,78,79,80]. Also, SAC, DATS, and DAS inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor, decreasing the expression of different proinflammatory cytokines, such as tumor necrosis factor alfa (TNFα), interleukin (IL)1β, IL6, monocyte chemoattractant protein-1 (MCP-1), and IL-12
[59][60][81,82]. Due to these properties, garlic-derived compounds have been evaluated in different ischemic stroke models, showing a neuroprotective effect against the damage induced by brain ischemia
[53][60][76,82].
In vitro models, SAC shows protection against OGD/reoxygenation insult, increasing viability
[61][83] and decreasing apoptosis
[58][80] through the inhibition of the ERK
[53][76], c-Jun N-terminal kinase (JNK), and 38-kDa mitogen-activated protein kinase (p38) pathways and the activation of the Nrf2 pathway
[58][80]. Allicin and alliin prevent the decline of cellular viability induced by OGD/reoxygenation
[61][62][83,84].
Furthermore, garlic OSCs also promote brain protection in focal brain ischemia models. SAC administered before ischemia decreases neurological deficit and infarct volume, preventing the activation of the ERK1/2
[53][76], JNK, and p38 pathways
[58][80]. Additionally, it reduces oxidative stress, and increases glutathione (GSH)
[63][89] and antioxidant defense levels (HO-1, glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase regulatory subunit (GCLM)) through the Nrf2 pathway
[58][80], as well as the activity of the antioxidant enzymes glutathione reductase (GR), glutathione peroxidase (GPx), SOD, and CAT
[64][90]. Also, SAC reduces the increase in glial fribillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) levels
[64][90], resulting in the improvement of neurological deficits
[58][63][80,89] and a reduction in infarct volume and brain edema
[58][63][64][65][80,86,89,90].
3.3. Garlic Preparations as Treatment for Ischemic Stroke
Commercial garlic products, which contain a mixture of different OSCs, also show protection against global brain ischemia. Pretreatment with aqueous garlic extract reduces inflammation
[66][96], whereas garlic oil decreases infarct volume and lipoperoxidation, and improves short-term memory and motor coordination
[67][97]. In focal brain ischemia, AGE, aqueous garlic extract, and garlic clove and skin extracts (GCE and GSE) show brain tissue protection. AGE decreases neurological impairment, infarct area, and brain edema by reducing oxidative stress and inflammation
[65][68][69][86,98,99] and increasing GLUT3 transporter
[70][91]. Aqueous garlic extract improves neurobehavioral problems, diminishes cell death, and enhances antioxidant defense
[71][100]. GCE and GSE reduce cell damage and increase mitochondrial membrane potential and ATP levels, which could be associated with its scavenging activity against superoxide anions, peroxynitrite, hydroxyl radicals, and peroxyl radicals
[72][101].
3.4. Garlic Compounds and Neuroplasticity
The neurotrophic effects of SAC include an increase in axonal branching, neurite length, and the number of neurites in hippocampal neuron cultures. The changes in the morphology of neurons are related to better efficiency of the transmission and information processing ability of the neural network
[73][74][102,103]. Also, after cell damage triggered by excitotoxic insult with quinolinic acid, SAC treatment increases the levels of the neurotrophin BDNF, antioxidant defenses (HO-1) through the Nrf2 pathway, and ERK1/2 phosphorylation levels
[75][104].
SAC is the OSC that is most studied in vivo, and its trophic effects have been proven in different models. Treatment administered for 21 days to young healthy animals increases the number of positive cells to marker of proliferation Ki67 (Ki67) and the marker of neuroblast differentiation (doublecortin) in the SGZ of the dentate gyrus in the hippocampus. Furthermore, SAC increases serotonin 1 A receptor levels, and the activation of these receptors increases neurogenesis in the dentate gyrus
[76][107]. Also, it improves memory in senescence-accelerated animals, or damage due to streptozotocin or lipopolysaccharide
[74][77][78][103,108,109]. Senescence-accelerated mouse prone is a model for aging and age-related disorders that has a short lifespan and age-dependent pathologies like impairment in learning and memories. The improvement in memory in senescence-accelerated mouse prone treated with SAC was accompanied by the preservation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR, and phosphorylated α-calcium/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus; these proteins are related to the maintenance of learning and memory functions
[74][103].
The intraventricular streptozotocin administration model produces cognitive deficits and oxidative damage in the hippocampus. SAC prevents cognitive and neurobehavioral impairments, increases the antioxidant state (GSH, GPx and GR), and diminishes thiobarbituric acid-reactive substances (TBARS) and apoptotic parameters (DNA fragmentation, the expression of B cell lymphoma 2 (Bcl-2) and tumor protein p53 (p53))
[77][108]. Similarly, lipopolysaccharide administration induces learning and memory impairment and neuroinflammation. SAC improves memory, mitigates lipid peroxidation (malondyaldehyde) and augments SOD, GSH, and acetylcholinesterase activity. Furthermore, it downregulated hippocampal NF-κB, Toll like receptor 4 (TLR4), GFAP, IL-1β, and ionized calcium-binding adaptor molecule (Iba1) and upregulated Nrf2
[78][109].
The other OSCs that have shown an increase in memory performance after injury are the allicin and Z-ajone
[79][80][111,112]. The effects of allicin have been mainly related to morphological modifications, increasing the density of the dendritic spine, and synaptophysin and glutamate receptor-1 levels, indicating the formation of new synapses
[79][111]. As mentioned before, the formation of new synapses after stroke has been linked to functional and cognitive recovery. Z-ajone has inhibitory effects against memory impairment induced by scopolamine
[80][112].
Essential oils from two Allium species administered for 21 days to healthy animals increase memory, cell proliferation, and neuroblast differentiation in the dentate gyrus by increasing BDNF and acetylcholinesterase levels
[81][114]. Also, after chronic mild stress, treatment with garlic oil diminishes depressive-like behavior, increasing serotonin and dopamine levels through the activate BDNF/AKT/CREB pathway in the hippocampus
[82][113]. Aqueous garlic extract decreased blood lead levels and increased the neuroblast number (doublecortin-positive cells) in the dentate gyrus of 21-day-old offspring rats
[83][115]. In the case of memory deficits caused by diabetes, cognitive impairment was related to the alteration of the fluidity of the membranes, inhibiting Na+/K+ ATPase and Ca2+ATPase. In that work, ethanolic garlic extract augmented the activity of both ATPases and glutamine synthetase in animals with diabetes
[84][116]. Glutamine synthetase is an enzyme that is important in controlling the intracellular concentration of glutamate. The accumulation of glutamate in the extracellular fluid decreases the levels of glutamine synthetase, which may lead to seizures
[84][116].
4. Conclusions
Different garlic OSCs and preparations have been extensively utilized in preclinical studies for treating stroke. Their protective properties are principally attributed to their antioxidant and anti-inflammatory capacities assessed during short periods of ischemia and/or reperfusion. However, the mechanisms activated over longer periods, such as neuroplasticity, that are essential for effective patient recovery have not been studied. Despite this, both garlic compounds and preparations can stimulate neuroplasticity in healthy animals and models of neurological damage, suggesting that garlic compounds and preparations might stimulate neuroplasticity in ischemic stroke. Although this is a process that occurs after ischemic stroke, it requires an antioxidant and anti-inflammatory environment to ensure the survival of the new neurons and the proper functioning of connections between pre-existing neurons.