1. Introduction

Brain disorders represent a serious threat to human health because of both their high prevalence, which continues to rise in line with increasing life expectancy, as well as their associated disabilities, heavy economic burden, and lack of effective and tolerable treatments [1]. According to a World Economic Forum report [1], the global percentage of individuals aged more than 60 years will double from 11% in 2010 to 23% in 2050. Consistent with aging of the population, cardiovascular diseases, neurodegenerative conditions, and mental health conditions have now become the dominant contributors to the global burden of non-communicable diseases (NCDs). In fact, mental health conditions are now the leading cause of Disability Adjusted Life Years (DALYs), accounting for 37% of healthy life years lost from NCDs, and their global cost is expected to surge from $2.5 trillion USD in 2010 to $6.0 trillion USD by 2030 [1]. Neurodegenerative and neuropsychiatric conditions are usually treated symptomatically and currently available drugs generally lack disease-modifying activity, have low efficacy, and/or significant tolerability burdens [2,3,4,5,6]. Hence, there is an urgent need to identify more effective, low-cost, and easily scalable interventions to prevent and treat neurological, neurodegenerative, and psychiatric disorders.

A growing body of evidence indicates that exercise is effective in the prevention and treatment of various chronic disorders (reviewed in Reference [7]), including neurodegenerative and neuropsychiatric conditions. A dipeptide, carnosine (β-alanine-L-histidine), was identified as an exercise enhancer and has been widely used in sports with the aim of improving physical performance and muscle gain [8]. Carnosine has been shown to favourably affect energy and calcium metabolism, and reduce lactate accumulation [9,10]. Notwithstanding the biochemical complexity of exercise, both exercise and carnosine may exert similar effects including optimization of energy metabolism, improvement of mitochondrial function, and reduction of systemic inflammation, and oxidative stress [11,12,13]. Although 99% of carnosine in the human body is located in skeletal muscle, carnosine is also present in heart muscle as well as in specific areas of the brain at approximately 100-fold lower concentrations [10,12]. Thus, carnosine is found primarily in the two tissues with the most active oxidative metabolism, which are tissues in muscles and the brain. Both of carnosine’s precursors, β-alanine and L-histidine, can be easily taken up from circulation into the brain through amino acids transporters in the blood-brain barrier (BBB) [14]. This enables local carnosine synthesis in the brain, which takes place in olfactory neurons [15] and in glial cells, specifically in mature oligodendrocytes [16,17]. Carnosine itself can also cross the BBB [18], but it is thought that the majority of brain carnosine is a product of its de novo synthesis localized to specific areas of the brain rather than a result of its penetration through the BBB [12]. Carnosine together with homocarnosine, which is a dipeptide of gamma-aminobutyric acid (GABA) and histidine and the dominant carnosine analogue in the human brain, are both present in cerebrospinal fluid (CSF) [16].

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The presence of carnosine and its analogues in the brain suggests that these histidine-related compounds may play some physiological role in brain function, as endogenous antioxidants, neuromodulators, and neuroprotective molecules [12]. However, despite a number of studies demonstrating the anti-ischemic and neuroprotective properties of carnosine, there is currently no unified hypothesis as to the exact role of carnosine in brain disorders, or its potential use in preventing or managing these conditions. Although previous reviews including systematic reviews and meta-analyses on this topic have been conducted, these tend to focus on specific disorders such as neurodegenerative disorders [19] or depression [20], or are limited to human studies, overlooking the large body of evidence derived from experimental and animal models. Given these limitations and the considerable number of newly published studies, a comprehensive updated review of the evidence in relation to carnosine and brain-related disorders is pertinent.

In this narrative literature review, we aimed to summarize current evidence regarding the potential role of carnosine in brain-related disorders, including neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders from cell, animal, and human studies including clinical trials and meta-analyses. We did not intend to introduce new data or conclusions but rather to integrate and contextualise the current state of knowledge in this area and to identify relevant evidence gaps. For the purpose of this review, we define neurological disorders as those conditions with recognisable pathological damage to the brain (e.g., ischemia/stroke), neurodevelopmental disorders as abnormal brain development (e.g., Autistic spectrum disorders), neurodegenerative disorders as involving cell death and degeneration over time (e.g., Alzheimer’s, Parkinson’s), and psychiatric disorders as those which affect mental functioning and behaviour (e.g., schizophrenia, mood disorders). We searched relevant publications in PubMed using the following keywords without date limits including both clinical and preclinical data: carnosine, β-alanine, L-histidine, anserine, dementia, cognition, Alzheimer disease, mild cognitive impairment, Parkinson disease, multiple sclerosis, stroke, brain ischemia, brain hemorrhage, brain trauma, epilepsy, Autistic spectrum disorders, mood disorders, anxiety, depression, schizophrenia, Attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, post-traumatic disorder, and dyslexia.