6.1. The reduction of oxidative stress
The ALS treatment at the stage of clinical manifestations, due to the insignificant influence of the initiating factors of the disease in this period, as compared to the prevailing significance of oxidative stress, should probably include the use of antioxidants with a wide range of mechanisms of action, affecting as many pathogenetic pathways as possible.
As of today, the main antioxidant, that is FDA approved and used in clinical practice for ALS patients is edaravone, which is a free radical acceptor and has shown significant effectiveness during clinical trials, has demonstrated the ability to slow down the progression of the disease by an average of 35% .
Another drug – masitinib is currently in the third phase of clinical trials, has shown the efficacy several years ago. By the means of inhibiting the class III receptor tyrosine kinase (TRK III), it can increase the life expectancy of sALS patients by, on average, 25% .
Melatonin exhibits antioxidant properties by activating glutathione peroxidase, inhibiting NO synthase, and reducing mitochondrial dysfunction [72, 73]. In a study involving ALS patients, melatonin was able to improve laboratory parameters, however it didn’t affect the clinical parameters .
Alpha-lipoic acid is a cofactor of mitochondrial enzymes and promotes mitochondrial function restoration. During the study with transgenic mice, it has shown a significant effect in the form of improved motor function and increased survival rate .
It has also been shown that ginseng extracts facilitate the reduction of Ca2+ influx into neurons. In transgenic mice models ginseng effectively reduced the severity of symptoms and increased survival rate as well .
Ginkgo biloba extract EGb761 both counteracts the formation of ROS and aldehydes and increases the activity of glutathione peroxidase and catalase. In addition, it activates the antiapoptotic factor Bcl-2 . When tested in transgenic mice models, Ginkgo biloba extract increased survival rate and decreased the loss of motor neurons. However, the effect was present only in males .
L-carnitine normalizes mitochondrial function. It has demonstrated the ability to increase survival rate, as well as motor function and to decrease clinical manifestations of ALS in transgenic mice models .
Resveratrol, a natural polyphenol capable of exerting a protective effect both through a direct antioxidant effect on reactive oxygen species and through the activation of Sirtuin 1, had a positive effect on the course of ALS in the SOD1 mouse model of ALS, delaying the onset of the disease and slowing down its course .
Quercetin, another polyphenol that displays neuroprotective effect through several pathways , has also been shown to be effective in mouse models [82, 83].
Curcumin, a polyphenol that can both suppress neuroinflammatory processes and improve mitochondrial function under conditions of oxidative stress [84, 85], in particular, caused by TDP-43 pathology [86, 87], has shown significant efficacy in patients with sALS [88, 89].
Co-enzyme Q10, as a cofactor in ETC and a free radical scavenger , led to an increase in lifespan in the SOD1 mouse model of ALS  and a decrease in mitochondrial dysfunction in patients with sALS .
Epigallocatechin-3-gallate (EGCG), in turn, being able to activate excitatory amino acid transporter 2 (EAAT2) on astrocytes surface, promotes the elimination of glutamate from the synaptic cleft . EGCG has also been shown to improve mitochondrial function under conditions of oxidative stress . When studied in transgenic mice, the EGCG prolonged survival, reduced clinical manifestations of the disease, and also significantly reduced the level of oxidative stress markers [95, 96].
Astaxanthin and lycopene are carotenoids capable of neutralizing reactive oxygen species to a significant extent, providing a pronounced antioxidant effect . A study showed their ability to successfully counteract oxidative stress in a culture of motor neurons , while another study suggests that their use can reduce the risk of developing ALS [99, 100].
Bacopa monnieri extract may also be effective in overcoming excitotoxicity and oxidative stress in ALS due to its ability to increase the expression of the GluA2 subunit of the AMPA receptor .
Cannabinoids such as tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been proven to exhibit a pronounced antioxidant effect by reducing Ca2+ levels in neurons . These compounds have shown efficiency in transgenic mouse models, increasing survival rate, reducing weight loss, and slowing down the loss of motor function .
Vitamin E affects primarily H2O2, O2- and OH. . Even though vitamin E did not have a noticeable effect on clinical manifestations in ALS , many studies have shown that its intake significantly reduced the risk of death from sALS [106, 107, 108].
Creatinine regulates the uptake of glutamate by cells as well as stabilizes mitochondrial membranes. During research, although it showed promising effects in transgenic mice models, it did not appear to be effective during clinical trials .
Ceftriaxone acts as an antioxidant by activating EAAT2 on astrocytes. During both the first and second phases of clinical trials ceftriaxone showed extremely promising results, however during the third phase no pronounced effect has been detected .
EH301 is a combination of pterostilbene and nicotinamide riboside. Pterostilbene is a polyphenol that has a higher bioavailability than resveratrol, which belongs to the same class (stilbenes)  and is capable of both direct antioxidant effect and indirect anti-inflammatory and antioxidant effects [112, 113], primarily due to the activation of SIRT1 .
Pterostilbene is also capable of exerting an antiviral effect, including effects against entero- and retroviruses . Nicotinamide riboside is an NAD + precursor that, similar to pterostilbene, can activate sirtuins  and, in addition, poly(ADP-ribose) polymerases (PARPs) , thus exerting a powerful restorative effect on cellular metabolism . The combination of pterostilbene and nicotinamide riboside in the form of EH301 has been shown to have a significant therapeutic effect, slowing down the progression of the disease and improving clinical parameters , while being safe .
AMX0035, a combination of sodium phenylbutyrate and tauroursodeoxycholic acid, showed extremely positive results in a double placebo-controlled study, significantly slowing down the progression of the disease .
Memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, significantly slowed disease progression and increased lifespan in mouse models .
In addition, preliminary, clinical efficacy in ALS patients was demonstrated for an anti-inflammatory drug, the phosphodiesterase inhibitor ibudilast, clinical trials for which are currently ongoing .
At the same time, a phytoestrogen genistein is not only an antioxidant, but also capable of displaying both antiretroviral and anti-enteroviral activity [124, 125]. When tested in transgenic mouse models of ALS, its administration led to a reduction in symptoms and prolongation of survival, however, only in males .
To summarize, although some of the listed substances and drugs, which showed a positive effect in animal models and in case of prophylactic use subsequently did not have the same effect on ALS patients, the author is inclined to believe that in ALS only complex measures against oxidative stress is reasonable, with the simultaneous administration of various antioxidants (so-called “mitochondrial cocktail” ), which as a group can have a potentiating effect, altogether exhibiting a more pronounced effect than each one of them individually.
6.4. Anti-enteroviral therapy
Since PAANPEVs is currently the only factor that could be determined as the initiating factor in the sALS pathogenesis, the therapeutic measures aimed against it should be the basis for the treatment of this disease, especially at the preclinical stage.
Ribavirin is a well-known drug with proven activity in NPEVs-induced (including PAANPEVs) lesions of the CNS . More recently, a paper has been published demonstrating the impressive efficacy of ribavirin in CVB3-induced ALS-like disease in mice, and specifically in case of early administration . These results, as well as the theoretical rationale for the use of ribavirin in sALS, are promising.
In addition, certain lactic acid bacteria, such as Lactobacillus plantarum and Lactobacillus amylovorus, are also likely to have anti-enteroviral activity [133, 134]. Moreover, it has been shown that in ALS the disturbances in the balance of the intestinal microbiota are present .
As it has been shown, to date, there is no direct-acting treatment for sALS, as well as there are no theoretical candidates for this role. Nevertheless, the prospect of sALS treatment, or at least significant slowing down of its progression, still seems possible. Many of the drugs and substances described in this paper are likely to influence the course of sALS. Among such drugs are those that have already shown their effectiveness in clinical trials, for example, AEOL-10150, arimoclomol, and ceftriaxone, as well as the ones that have a convincing theoretical basis and have shown promising results when tested in transgenic mice models or cell culture, but for some reason were not subject to further investigation and clinical trials, such as EGCG, Δ9-THC, L-carnitine, genistein and alpha-lipoic acid. Both antiretroviral and anti-enteroviral drugs deserve special attention, in particular – ribavirin, which, if the proposed model of sALS pathogenesis is correct, can be defined as the first theoretical drug for the etiotropic treatment of sALS. Thus, there is a vital need for its detailed research and clinical trials.
It should also be taken into consideration, that ALS is a disease, the pathogenetic structure of which at the time of the onset of symptoms seems to be extremely heterogeneous and includes the continuing influence of initiating factors such as PAANPEVs infection, TDP-43 pathology, and HERV-K reactivation as well as the numerous consequences of these factors: from oxidative stress to massive cytoplasmic proteins aggregation. All the mentioned leads to conclusion that at the clinical stage of ALS there simply cannot be one drug, on the contrary, the treatment must be complex. That is, the treatment must consist of a group of drugs and substances that altogether could affect the maximum number of mechanisms and pathways involved in the ALS pathological process.
Of all the above-mentioned compounds, the author singles out ribavirin as a particularly interesting and potentially effective drug worthy of conducting clinical trials in sALS, due to its potential effect on one of the key and early elements in pathogenesis - enteroviruses. In case of its effectiveness, in particular, at the preclinical stages of sALS, probably, given the specificity of the disease, the conduction of clinical trials of complex sALS therapy, consisting of theoretically and practically founded combination of antioxidants, antiretroviral and anti-enteroviral therapy based on ribavirin should be considered.
In addition, once again, given the specificity of the disease, as well as the known relative safety of antioxidant drugs, there possibly is a basis for the experimental prescription in clinical practice, especially in patients with a rapid rate of sALS progression, of a combination of antioxidant drugs, selected in such a way that impact on as many OS processes as possible.