**7. Clinical applications and perspectives**

The first (and obvious) clinical application of AAs is as a reference level to indicate different pathologies. This suggestion covers more AAs than those mentioned above. For decades, the biochemical analysis of AAs in body fluids has been an important diagnostic tool in the detection of congenital errors of metabolism. Significant elevations of amino acids in plasma, urine, or CSF have been the backbone of many diagnostic procedures [71]. This is because defects in amino acid catabolic pathways can be detected by the characteristic accumulation of their metabolites. Well-known examples of this are elevated plasma concentrations of phenylalanine in phenylketonuria (PKU) and increased concentrations of homocysteine in homocystinuria [71].

In addition, the properties of glutamate/glycine discussed above indicate a wide range of potential medical applications for compounds that govern transport, receptors, and metabolic systems in the CNS. A classic pharmacological approach may be based on the search for chemicals that affect the indicated processes; interactions with the target protein site or reaction must be local and precisely unidirectional and wide metabolic participation of the candidate should be avoided. There are several examples to date. Each of the three mGlu subgroups can be considered a novel target for the treatment of schizophrenia. All three symptom domains could be effectively treated by mGlu5 positive allosteric modulators, which are devoid of toxicity and seizure liability according to preclinical data. Furthermore, the potential antipsychotic and cognitive-enhancing effects of drugs targeting mGlu1 and mGlu3 were supported by recent genetic investigations of schizophrenia patients [72]. Preclinical studies have revealed that specific mGluR subtypes mediate significant neuroprotective effects that reduce toxin-induced midbrain dopaminergic neuronal death in animal models of Parkinson's disease [41]. Additionally, mGluRs have emerged as research targets in treating Alzheimer's disease. In particular, mGluR-based compounds producing both symptomatic and disease-modifying effects in preclinical models of the disease are of special interest [73]. G proteincoupled mGluRs expressed by tumor cells, particularly cancer stem cells, might

#### *Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition… DOI: http://dx.doi.org/10.5772/intechopen.103760*

represent new candidate drug targets for the treatment of malignant brain tumors [74]. Group III mGluR agonists have been recently identified as promising tools for managing affective symptoms, such as the pathological anxiety observed in neuropathic pain. However, the use of mGluR ligands as anxiolytics was disappointing in clinical trials. Nevertheless, there is ground for a certain amount of optimism [75].

Pharmacological modulation of glycinergic inhibition could represent a novel therapeutic strategy for a variety of diseases involving altered synaptic inhibition, primarily in the spinal cord and brain stem but possibly also at supraspinal sites [74]. Among the inhibitors of GlyT-1, two candidates have attracted the most attention. Sarcosine, a known intermediate of glycine metabolism, had positive results as a short-term treatment of major depression and for acutely ill and chronically stable schizophrenia patients. Another GlyT-1 inhibitor, bitopertin, was expected to be effective in treating negative or positive schizophrenia symptoms. However, the phase III clinical trials fell short of the primary endpoint, and the investigation was halted due to its lack of efficacy in improving negative symptoms [76]. Gelsemium, a small genus of flowering plants from the family Loganiaceae, may be used as a pain treatment and for its mechanism of action. Gelsemium and its active alkaloids may produce antinociception by activating the spinal α3 glycine/allopregnanolone pathway in inflammatory, neuropathic, and bone cancer pain without inducing antinociceptive tolerance, in contrast to morphine [75].

Another strategy is to directly use AAs for medical treatment. In this scenario, glycine is the most appropriate candidate. Glycine has a wide spectrum of protective properties against different diseases and injuries. As such, it represents a novel anti-inflammatory, immunomodulatory and cytoprotective agent [77]. Oral supplementation of glycine at a proper dose is very successful in treating several metabolic disorders in individuals with cardiovascular diseases, various inflammatory diseases, cancers, diabetes, and obesity [34]. Glycine was well tolerated at a dose of 0.8 g/kg body weight a day, resulting in significantly increased serum glycine levels and a 7% reduction in negative symptoms in patients with treatment-resistant schizophrenia [78]. An acute high dosage of glycine attenuates the neurophysiological representation of the brain's preattentive acoustic change detection system (mismatch negativity) in healthy controls, raising the possibility that the optimal effects of glycine and other glycine agonists may depend on the integrity of the NMDA receptor system [79]. The glycine was effective in the treatment of ischaemic stroke patients. In a randomized, double-blind, placebo-controlled study on 200 patients with acute (<6 h) ischaemic stroke in the carotid artery area, 1.0–2.0 g/day of glycine was accompanied by a tendency towards decreased 30-day mortality (5.9% in the 1.0 g/day glycine and 10% in the 2.0 g/day glycine groups vs. 14% in the placebo and 14.3% in the 0.5 g/day glycine groups), an improved clinical outcome on the Orgogozo Stroke Scale (p < 0.01) and the Scandinavian Stroke Scale (p < 0.01) and a favorable functional outcome on the Barthel Index for Activities of Daily Living (p < 0.01) in the 1.0 g/day glycine group compared to those in the placebo group in patients with no or mild disability [80]. The molecular mechanism of such an effect is based on the ability of glycine to initiate stable vasodilatation of arterioles, which has been demonstrated in rat pial vessels and in mesenteric arterioles [81, 82].

### **8. Conclusions**

According to experimental and clinical evidence, AAs are especially useful nutrients for the treatment of patients with different diseases. These nutrients not only supply a background pool for biochemical reactions, but the functions of the metabolites cover a wide range of neurochemical processes, and they are always

**Figure 5.**

*Scheme of the mutual influence of inhibition and excitation mediated by glycine and glutamate.*

mutually dependent. Even though some processes are decreased or increased in illnesses, it does not mean that the treatment strategy must be targeted to only correct the single altered process. A prominent example is glutamate-induced excitotoxicity in neurons. The best strategy to prevent increased glutamate concentrations is to maintain bioenergetic processes in neurons and astrocytes at high activity levels and to activate glycine-dependent processes. Moreover, it helps to assign the exceeded content of the neuromediator to a physiological range and to form stable conditions for further health development, avoiding excitotoxicity (**Figure 5**). Searching for exogenous antagonists of metabolic receptors seems to be an incorrect therapeutic strategy because the function of the AA-dependent system depends on the basic metabolic regulatory core of metabolic processes. Indeed, to find appropriate therapeutic methods, further fundamental and clinical investigations are necessary.
