CARNOSINE SCIENCE:

🧠 Carnosine and Neurological Disorders

Reviews

The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence

by Martin Schön 1,2,Aya Mousa 3ORCID,Michael Berk 4,5,Wern L. Chia 3,Jozef Ukropec 2ORCID,Arshad Majid 6,Barbara Ukropcová 1,2,7,* andBarbora de Courten 3,*ORCID

✅ Abstract:

Neurological, neurodegenerative, and psychiatric disorders represent a serious burden because of their increasing prevalence, risk of disability, and the lack of effective causal/disease-modifying treatments. There is a growing body of evidence indicating potentially favourable effects of carnosine, which is an over-the-counter food supplement, in peripheral tissues. Although most studies to date have focused on the role of carnosine in metabolic and cardiovascular disorders, the physiological presence of this di-peptide and its analogues in the brain together with their ability to cross the blood-brain barrier as well as evidence from in vitro, animal, and human studies suggest carnosine as a promising therapeutic target in brain disorders. In this review, we aim to provide a comprehensive overview of the role of carnosine in neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders, summarizing current evidence from cell, animal, and human cross-sectional, longitudinal studies, and randomized controlled tria

✅ Conclusion:

Several lines of evidence, particularly from cell and animal studies, demonstrate potential effects of carnosine on brain-related disorders and the mechanisms underlying these disorders including anti-oxidative, anti-inflammatory, chelating, anti-apoptotic, and anti-glycating properties. These mechanisms were investigated using animal models of various brain pathologies. However, caution is urged when extrapolating these findings to the human context, especially since the levels of carnosinase are much lower in rodents than in humans [10]. Furthermore, dosages of carnosine used in animal studies usually far exceed physiological concentrations in humans. Nevertheless, provisional human studies have shown promising results of supplementation with carnosine or its precursors in specific cognitive functions, improvements in core or secondary symptoms of ASD, schizophrenia, fatigue related disorders, ADHD, and OCD or augmentation of standard treatment of PD. Well designed and adequately powered trials in these disorders are warranted. Despite promising results from studies exploring the effects of carnosine and its derivatives on health, one should bear in mind that the development and pathophysiology of neurodegenerative, neurological, and psychiatric disorders are strongly affected by various risk factors including lifestyle habits, and the supplementation with dietary supplements is not sufficient to compensate for the lack of physical activity and/or the unhealthy diet.

Antioxidant and Neuroprotective Effects of Carnosine: Therapeutic Implications in Neurodegenerative Diseases

Cristina Solana-Manrique 1 2, Francisco José Sanz 1 2, Guillermo Martínez-Carrión 1 2, Nuria Paricio 1 2

Web Link - https://www.mdpi.com/2076-3921/11/5/848

✅ Abstract:

Neurodegenerative diseases (NDs) constitute a global challenge to human health and an important social and economic burden worldwide, mainly due to their growing prevalence in an aging population and to their associated disabilities. Despite their differences at the clinical level, NDs share fundamental pathological mechanisms such as abnormal protein deposition, intracellular Ca2+ overload, mitochondrial dysfunction, redox homeostasis imbalance and neuroinflammation. Although important progress is being made in deciphering the mechanisms underlying NDs, the availability of effective therapies is still scarce. Carnosine is a natural endogenous molecule that has been extensively studied during the last years due to its promising beneficial effects for human health. It presents multimodal mechanisms of action, being able to exert antioxidant, anti-inflammatory and anti-aggregate activities, among others. Interestingly, most NDs exhibit oxidative and nitrosative stress, protein aggregation and inflammation as molecular hallmarks. In this review, we discuss the neuroprotective functions of carnosine and its implications as a therapeutic strategy in different NDs. We summarize the existing works that study alterations in carnosine metabolism in Alzheimer's disease and Parkinson's disease, the two most common NDs. In addition, we review the beneficial effect that carnosine supplementation presents in models of such diseases as well as in aging-related neurodegeneration.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; carnosine; inflammation; neurodegenerative diseases; neuroprotective effect; oxidative stress; protein aggregation; therapeutic approach.

✅ Conclusion:

Carnosine is an endogenous dipeptide that has been widely studied due to its multiple effects. Among them, carnosine has been shown to exert antioxidant, anti-inflammatory, anti-glycating and anti-aggregant properties [9,13,20]. Interestingly, most of these activities directly impact processes such as OS, neuroinflammation, protein glycation/aggregation, etc., which are relevant for the onset/development of several NDs [2,3]. However, carnosine metabolism has been scarcely studied in such diseases. Despite this, the results obtained to date point to a general reduction in carnosine levels in NDs such as AD or PD (see Section 4). Interestingly, alterations in carnosine metabolism have been also related to other disorders such as diabetes or cardiac alterations [110,111]. Several approaches have been carried out to increase carnosine levels in models of those diseases. For instance, it has been reported that CARNS1 overexpression in mice was able to protect heart from ischemia reperfusion injury [18]. In addition, compounds able to reduce CN activity such as bestatin, an allosteric CN2 inhibitor, have been reported to be beneficial in the retina of a diabetes mouse model [112].

Currently, existing therapies for NDs are only symptomatic and are not able to reduce or stop their progression [4]. Given the multimodal mechanism of action of carnosine, along with the finding that its levels are reduced in several NDs, this dipeptide has been postulated as a promising therapeutic for such diseases. In fact, carnosine supplementation has been evaluated in several models of AD and PD, in humans, as well as in aging-related neurodegeneration, finding that it was able to alleviate some of their most characteristic phenotypes (see Section 5 and Table 2). In addition, one clinical trial was conducted to evaluate carnosine supplementation in three patients with multiple sclerosis (NCT03995810). Results showed that, at eight weeks of supplementation, it was able to attenuate symptomatology in those individuals [113]. Another clinical trial was initiated in 2017 in early-stage PD patients (NCT03330470); however, no results have been published yet. Therefore, the therapeutic potential of alternative strategies already used in other human diseases and directed toward increasing endogenous carnosine levels should be further evaluated in NDs such as PD and AD.

Neuroprotective Effect of Carnosine Is Mediated by Insulin-Degrading Enzyme

Alessia Distefano 1, Giuseppe Caruso 2 3, Valentina Oliveri 1, Francesco Bellia 4, Diego Sbardella 5, Gabriele Antonio Zingale 1, Filippo Caraci 2 3, Giuseppe Grasso 1

✅ Abstract:

l-Carnosine is an endogenous dipeptide that has high potential for therapeutic purposes, being an antioxidant with metal chelating, anti-aggregating, anti-inflammatory, and neuroprotective properties. Despite its potential therapeutic values, the biomolecular mechanisms involved in neuroprotection are not fully understood. Here, we demonstrate, at chemical and biochemical levels, that insulin-degrading enzyme plays a pivotal role in carnosine neuroprotection.

Keywords: Alzheimer’s disease; IDE; carnosine; diabetes; insulin; neuropeptides.

✅ Conclusion:

As experts in the field continue to advertise, “many of the most exciting new possibilities hinge on the development of powerful pharmacological modulators of IDE.” 59 Car is an endogenous peptide that can be also given orally as a betaalanine supplement, widely used by many people, especially athletes to improve their performances.60 Although the presence of Car in the serum is not detectable because of its rapid degradation by serum carnosinase,61 intact Car is excreted in urine up to 5 h after intake, indicating that the dipeptide resists somehow to degradation.62 As it is widely reported that Car is neuroprotective,63 here we have explored the possibility that Car exerts its beneficial effect through the modulation of IDE. Our results obtained in rat mixed neuronal cultures clearly show that Car is protective against Aβ1−42- induced toxicity and also that the neuroprotective activity of Car is lost in the presence of 6bK, a highly selective IDE inhibitor, supporting the recent findings described by Fu et al.18 demonstrating that microglia partially degrade Aβ via the secretion of IDE. In order to understand the molecular basis of such an intriguing result, we have applied various experimental approaches to assess the Car mechanism of action on IDE. Indeed, DLS measurements show that Car alters the average hydrodynamic radius of the enzyme, hinting to higher oligomeric forms induced by the presence of Car in a concentration-dependent manner. We exclude that the change in the hydrodynamic radius could be due to a change in enzyme conformation, as IDE R767A used to test such hypothesis did not show the same trend. In accordance to this result, SPR measurements applied to calculate the Hill coefficient gave a clear indication that Car directly affects the enzyme cooperativity, increasing the value of the Hill coefficient in a concentration-dependent manner. Last but not least, HPLC-MS experiments clearly show an increase in IDE activity toward both Ins and Aβ peptides in the presence of Car. On the contrary, the IDE degradation of a smaller fluorogenic substrate does not seem to be affected by the presence of Car. The latter findings give a clear indication on the possible mechanism involved in Car neuroprotection. Indeed, all results point at an IDE activating role of Car due to an increase in the oligomerization and in the cooperativity of the enzyme, which increase the enzyme capability to degrade long substrates such as Ins and Aβ peptides, but not shorter one such as substrate V. This specific regulatory mechanism indicates that Car does not bind to the IDE catalytic site, being a heterotropic modulator, as it is able to regulate the enzyme activity by binding to the exosite or to other not identified sites, causing a different interaction between the enzyme and long substrates, changing their reciprocal affinity and, in turn, IDE catalytic activity. Such a result is in accordance with previous findings already reported for IDE activity53,56 and opens a new path to explore the therapeutic potential of Car in AD.

1. Carnosine as a natural antioxidant and geroprotector: From molecular mechanisms to clinical trials
Authors: Boldyrev AA, Aldini G, Derave W.
Journal: Rejuvenation Research. 2010 Apr;13(2-3):156-64.


Summary: This review discusses carnosine's antioxidant properties and its potential role in neuroprotection and aging.


https://pubmed.ncbi.nlm.nih.gov/20017611/

✅ Abstract:

Carnosine is a neuroprotective dipeptide consisting of beta-alanine and L-histidine. It demonstrates a number of useful features, including stimulation of brain and muscle microcirculation and a rejuvenating effect on cultured cells. Its activity is based on its antioxidant and antiglycating action that, in addition to heavy metal chelation and pH-buffering ability, makes carnosine an essential factor for preventing neurodegeneration and accumulation of senile features. Recently, carnosine was successfully used to treat patients after brain stroke or patients with Parkinson disease. We conclude that carnosine can be recommended for patients under oxidative stress as a natural remedy having high efficiency and no side effects.

Clinical Studies

Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders
Authors: Chez MG, Buchanan CP, Aimonovitch MC, et al.
Journal: Journal of Child Neurology. 2002 Nov;17(11):833-7.
Summary: This study evaluates the effects of L-carnosine supplementation on children with autism, noting improvements in behavior and communication.

✅ Abstract:

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.

✅ Conclusion:

L-carnosine supplementation (800 mg daily for 8 weeks) resulted in significant improvements in several areas of functioning for children with autism spectrum disorders (ASD), particularly:

• Expressive and receptive language

• Socialization

• Behavioral regulation

• Sensory processing and awareness

📊 Key Findings:

• Children in the carnosine group showed statistically significant improvements in scores on the Gilliam Autism Rating Scale (GARS) and the Clinical Global Impression Scale compared to the placebo group.

Improvements were observed by both teachers and parents, indicating noticeable effects in real-world settings

Carnosine supplementation improves cognitive outcomes in younger participants of the NEAT trial

Author links open overlay panelTimothy E. O'Toole a b 1, Alok R. Amraotkar a b 1, Hong Gao a b, Clara G. Sears a b, Shesh N. Rai c, Mathias Basner d, Aruni Bhatnagar a b

✅ Abstract:

Some prior studies suggested that supplementation with carnosine or β-alanine can improve cognitive abilities and neurodegenerative disorders in certain elderly or at-risk populations. However, the efficacy of carnosine in improving cognitive performance in a healthy, adult population has not been assessed. We examined this as a post-hoc secondary outcome in the placebo-controlled, randomized Nucleophilic Defense Against PM Toxicity (NEAT) clinical trial (NCT03314987). Participants in this trial were instructed to take either cornstarch (placebo) or carnosine capsules (2g daily) for up to 12wk. Cognitive ability was assessed using the Cognition test battery, which consists of ten individual tests known to engage specific brain systems and covering a range of cognitive domains. Speed, accuracy, and efficiency were obtained for the whole battery as well as for each of the ten individual tests. Participant testing occurred at baseline, prior to randomization, after approximately 6wk of supplementation (Follow-up-1), and after approximately 12wk of supplementation (Follow-up-2). Of the 299 participants who were randomized, we obtained useable measures for 242 participants at Follow-up-1 and 231 ​at Follow-up-2. Age-based stratification (23–35 years, 36–50 years, 51–65 years), showed statistically significant improvements in overall speed and efficiency in the youngest age group stratum at both follow-up visits. This same group also demonstrated significant improvements in seven speed or accuracy scores of the individual tests. The other age groups demonstrated few or no significant improvements. Thus, in a study population largely devoid of susceptibility factors or pre-existing conditions, carnosine supplementation selectively improved high-level cognitive performance in young individuals.

✅ Conclusion:

In summary, we found that daily supplementation with carnosine improved cognitive efficiency, mostly by improving speed without sacrificing accuracy, across a range of cognitive domains. These benefits were particularly pronounced in younger members of the study cohort (23–35 years) and were minimal or not observed in older study participants. Routine or targeted supplementation with carnosine may be an effective means of improving high-level cognitive performance in the young.