Figure 3: Tissue-specific processes that occur following a course of LLLT that benefit a range of brain disorders. Brain-derived neurotrophic factor (BDNF); nerve growth factor (NGF); neurotrophin 3 (neurotrophin 3; NT-3); superoxide dismutase (superoxide dismutase; SOD). (Image content source: MR Hamblin / BBA Clinical 6 (2016) 113–124, redrawn by JoiiUp)

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neuroprotection

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Various evidences suggest that LLLT can be used for neuroprotection by inhibiting the activity of Glycogen synthase kinase 3 beta (GSK3β) to protect cells from damage, promote their survival and longevity, and reverse apoptotic signaling processes, Prevents apoptosis, the normal cell death that occurs as an organism grows. GSK3β is believed to act as a mediator between AKT and the Bax apoptotic gene, a protein that translocates to the nucleus in the presence of pro-apoptotic stimuli to trigger the initiation of this process. However, when GSK3β was inhibited, the communication path between AKT and AKT was cut off. As a result, Bax translocations cannot be expressed and are therefore suppressed [27].  

LLLT also exhibits neuroprotective effects in the form of protection against aging [28]. It has been shown to activate the extracellular signal-related kinase (ERK)/forkhead box protein M1 (FOXM1) pathway. The FOXM1 protein regulates the cell cycle from G1 to S phase, and by stimulating the ERK/FOXM1 pathway, LLLT results in greater ERK translocation to the nucleus and greater nuclear accumulation of FOXM1. This, in turn, leads to reduced expression of p21 protein and mitotic arrest in G1 phase, which slows down the progression of cellular senescence.  

LLLT has also been shown to effectively protect cells from toxins [29]. In a rodent model by Eells' group [30], exposure to methanol at 670 nm successfully restored retinal function and prevented tissue damage. This may be due to the fact that methanol generates the toxic metabolite formic acid (an inhibitor of CCO), and while LLLT is a known stimulator of CCO, the antitoxin effect of LLLT can be traced back to its stimulatory effect on CCO.  

Furthermore, LLLT has been shown to affect cells in different health states in different ways, essentially modifying cells in ways necessary to promote their survival. For example, in normal cells, absorption of light by CCO causes matrix metalloproteinases (MMPs) to rise above baseline and cause a transient increase in ROS production. However, in cells with low MMP in the presence of oxidative stress, excitotoxicity, or inhibition of electron transport, light absorption causes an increase in MMP towards normal concentrations and a decrease in ROS production [31]. Likewise, the typical response of healthy cells to LLLT is a transient increase in intracellular calcium [32]. However, in cells that already contain excess calcium ions (a phenomenon known as excitotoxicity), LLLT triggers the opposite response, in other words, it reduces the excess concentration of cellular calcium, which promotes cell survival, reduces oxidative stress and enables MMP returned to normal levels [33].

Oxidative stress

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Oxidative stress occurs when there is an imbalance between the body's ability to resist the action of reactive oxygen species and reactive oxygen species (ROS) production, and when reactive oxygen species are in excess, they become harmful through antioxidants. Many studies have shown that oxidative stress is associated with various neurological diseases, such as severe depression and traumatic brain injury, not to mention cardiovascular disease and Alzheimer's disease [34-37]. However, the situation is much more complicated than preliminary observations, as numerous clinical trials of antioxidant therapy for these diseases have failed [38]. Clearly, a certain level of oxidative stress is necessary for optimal functioning of humans, and removing all oxidative stress through supplementation with antioxidants may be counterproductive [39]. A major paper showed that the health benefits of exercise disappeared when antioxidants were taken [40].  

Salehpour's team [41] showed that sleep deprivation (SD) in mice induces oxidative stress in the hippocampus, which in turn leads to memory impairment. Transcranial treatment of LLLT with NIR (810 nm) (once daily for 3 days) delivered to the head, mice performed better on the Barnes maze and the What-Where-Which task with increased concentrations of antioxidant enzymes in the hippocampus, Decreased oxidative stress biomarkers. When studying the effects of LLLT on traumatized muscle, it was shown to effectively modulate the amount of cytokine-inducible nitric oxide synthase (iNOS) produced by the cells. This is important because excess iNOS leads to excess NO production, which triggers increased ROS/RNS (peroxynitrite) production, leading to increased oxidative stress. Specifically, LLLT can reduce peroxynitrite [42], while still retaining the positive effects of other isoforms of NO synthase, such as endothelial nitric oxygen synthase (eNOS), which is primarily responsible for Components of LLLT vasodilation [43, 44].  

LLLT has also been shown to stimulate an increase in angiogenesis, leading to further improvements in blood flow. As demonstrated by Cury [45], LLLT at 780 nm and 40 J/cm2 triggered increased protein HIF1α and vascular endothelial growth factor expression, as well as decreased matrix metalloproteinase 2 (matrix metalloproteinase 2) activity, which were found to Induce angiogenesis. In addition, when the effects of red/near-infrared on red blood cells were studied in vitro, near-infrared was found to be very effective in protecting red blood cells from oxidation [46], which is a common phenomenon in the brain afflicted by diseases such as severe depression [47] . Extensive mitochondrial dysfunction, increased levels of aluminum and heavy metals, and neuroinflammation that occur in AD generate substantial oxidative stress. Oxidative stress leads to Aβ deposition, tau hyperphosphorylation and subsequent synaptic and neuronal loss [48].

Anti-inflammatory effect

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Inflammation, one of the defenses of the innate immune system against foreign bodies such as bacteria and viruses, occurs at the cellular level when the transcription factor NF-κB is stimulated. While acute inflammation is helpful, chronic inflammation can have very detrimental effects. many diseases, including neurodegenerative diseases​​ Sickness and mood disorders can be attributed in part to chronic inflammation. One way LLLT helps calm inflammation is by inhibiting the cyclo-oxygenase 2 (COX-2) enzyme. Lim's research team [49] found that low-power 635 nm light irradiation could induce COX-2 inhibition by reducing intracellular ROS. Currently, the use of drugs to inhibit COX-2 is widely supported, with COX-2 inhibitors accounting for a large share of the NSAID market [50], and essentially the same results can be achieved using LLLT.  

LLLT can also modulate free NF-κB levels in cells. NF-κB can be found in the cytoplasm bound to the inhibitory protein IκB. Pro-inflammatory stimuli have the ability to stimulate IκB kinases, which are upstream signaling regulators that cause IκB degradation. After degradation of IκB, NF-κB can be freely transported to the nucleus, thereby triggering the expression of pro-inflammatory genes. There is evidence that LLLT can have opposing effects on NF-κB, depending on the cell type studied and its excitation state. Studies have found that in normal fibroblasts, LLLT can stimulate NF-κB by stimulating mitochondria to produce a small amount of ROS [51]. However, the same group found that in dendritic cells (another type of macrophage), which had been primed to an M1 phenotype, LLLT reduced proinflammatory cytokines [52]. Likewise, the Yamaura team found that NF-κB concentrations were reduced in activated rheumatoid arthritis synovial cells that received LLLT [53].  

In addition, LLLT has the ability to regulate the concentration of cytokines, which are important signaling molecules of the immune system. Studies have shown that LLLT can modulate the concentrations of pro- and anti-inflammatory cytokines, although its ability to modulate the concentrations of tumor necrosis factor (TNF) and other pro-inflammatory cytokines is particularly useful for reducing inflammation. It should be noted that inflammation within the brain has​​ significant difference. In fact, the term "neuroinflammation" is often used to excite microglia. Microglia function as an immune defense system in the central nervous system [54]. Microglia continuously clear the central nervous system of plaques, damaged neurons and synapses, and infectious agents.  

Microglia can assume a variety of phenotypes and retain the ability to alter their function to maintain tissue homeostasis. Microglia can be stimulated by LPS or IFN-γ to an M1 phenotype that expresses pro-inflammatory cytokines and can kill microbial cells. On the other hand, microglia can be stimulated to M2 type by IL-4/IL-13 to engulf debris, reduce inflammation and repair tissue. There is increasing evidence that metabolic reprogramming plays a role in the regulation of innate inflammatory responses [55]. Since there is substantial evidence that LLLT can stimulate mitochondrial metabolism to oxidative phosphorylation and away from aerobic glycolysis, this is how LLLT may change the microglial phenotype from M1 to M2. Reasonable cause [56]. The consequence of this transition is that LLLT-induced M2 can replace M1, which is unable to process substances such as beta-amyloid plaques in AD and thus produces ROS and inflammatory cytokines. In contrast, LLLT-induced M2 can clear plaques, exert anti-inflammatory and antioxidant effects, and promote tissue healing [57].

neurogenesis

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For years, the adult brain was thought to be incapable of growing new brain cells. Although it is recognized that the growth and development of the embryonic, young animal, and child brain must be enabled by neurogenesis mediated by neural stem cells (NSCs) and neural progenitor cells (neuroprogenitor cells), although this process begins in adulthood. has stopped. The turning point in our understanding was the discovery of adult neurogenesis and the identification of functions as NSCs, both in vitro and in vivo, that generate new neurons, glial cells [58].  

A study by Oron et al. is the first to report neurogenesis through stimulation of brain nerves by LLLT. In 2006, he induced in rats​​ stroke, and treated them with LLLT. When treated with LLLT, the number of newly formed neuronal cells and migrating cells was significantly increased in the ipsilateral subventricular region [59]. Similar results were found in Xuan's team, who used LLLT to treat mice with head trauma [60].

Promote synaptogenesis (Synaptogenesis)

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One of the most significant and potential effects of LLLT on the brain to date is its ability to promote synapse formation, also known as neuroplasticity. This process is critical as it can include head trauma, stroke, neurodegenerative diseases​​ Many brain conditions, including illness and mood disorders, can be traced, in part or in whole, to poor or abnormal neuronal connections in certain areas of the brain. If LLLT has the ability to counteract these effects by promoting neural tissue or reorganization, it could prove to be a new way to treat this type of brain disorder.  

One way that LLLT promotes neuronal connectivity may be by upregulating brain-derived neurotrophic factor (BDNF). BDNF is a protein found in the nervous system that helps maintain existing neurons and promotes the growth of new neurons and new synapses. Modulation of dendritic structure is believed to promote improved synaptic transmission [61]. LLLT has been shown to slow the decay of BDNF through the ERK/CREB (cAMP-response element binding protein; cyclic adenosine responsive element binding protein) pathway, thereby positively affecting dendritic morphogenesis and improving neuronal connectivity [62]. BDNF is also a mediator of the protein synapsin-1, which improves synapse formation by accelerating neuronal fiber development and maintaining synaptic contacts [63]. In a study by Meng's group [64], tighter branches and interconnectivity between fibers were observed in the neural tissue of embryonic rats under 780 nm light irradiation, suggesting enhanced activity of these proteins. BDNF is also associated with improved neuroplastic adaptation, which is especially important in the context of traumatic brain injury and stroke [65].  

If it can be conclusively demonstrated that LLLT stimulates neuroplasticity and synapse formation in humans as well as in mice, it would have opened the door to broad human clinical applications [66]. Impaired or abnormal neuroplasticity may be associated with a variety of brain disorders, such as Alzheimer's disease, psychiatric disorders, stroke, head trauma, and addiction [67-71].  

in conclusion

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Trials of drugs to treat brain injury from stroke or head trauma have been largely unsuccessful. Despite significant funding and research from academic labs and industry, progress on drugs to stop Alzheimer's and Parkinson's diseases remains elusive. Although psychiatric drugs such as antidepressants are well established and are among the best-selling drugs in the world, they are disappointingly effective and have a high chance of causing distressing side effects. Given LLLT's established safety profile, lack of apparent adverse effects, and relative cost-effectiveness, it is time to address the efficacy of LLLT for brain disorders.  

Overall, LLLT's prospects for treating brain diseases are very optimistic, and the relevant therapeutic mechanisms have also been confirmed by a large number of studies. With very positive results in animal model studies, and many small human clinical trials have been conducted so far, there is a need for more extensive clinical testing of LLLT and its use in neurological disorders of the brain without It has become a widely used treatment method.  

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