Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Abstract

Background and Purpose Despite the rapidly increasing global burden of ischemic stroke, no therapeutic options for neuroprotection against stroke currently exist. Recent studies have shown that autophagy plays a key role in ischemic neuronal death and treatments that target autophagy may represent a novel strategy in neuroprotection. We investigated whether autophagy is regulated by carnosine, an endogenous pleiotropic dipeptide which has robust neuroprotective activity against ischemic brain damage. Methods We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures. Results Autophagic pathways such as reduction of phosphorylated mTOR/p70S6K and the conversion of LC3-I to LC3-II were enhanced in the ischemic brain. However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling. The protective effect of carnosine against autophagy was also confirmed in primary cortical neurons. Conclusion Taken together, our data suggest that the neuroprotective effect of carnosine is at least partially mediated by mitochondrial protection, and attenuation of deleterious autophagic processes. Our findings shed new light on the mechanistic pathways that this exciting neuroprotective agent influences.

Ferulic acid attenuates brain microvascular endothelial cells damage caused by oxygen-glucose deprivation via punctate-mitochondria-dependent mitophagy

“…Both the inhibition of the fission machinery or the enhancement of mitochondrial fusion has been shown to decrease autophagy, and the enhancement of mitochondrial fusion can promote autophagy (Baek et al, 2014). Inhibition of the fission machinery through Drp1 dominant-negative K38A (Drp1K38A) or Fis1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins demonstrating that mitochondrial fission is essential for autophagy (Twig et al, 2008).…”

Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression

“…Moreover, autophagic pathways such as the mTOR pathway are closely related to the ischemic brain [30] . However, the regulatory network has not been fully explained.…”

Possible Benefit of Dietary Carnosine towards Depressive Disorders

“…Nevertheless it is possible that a common molecular entity exists whose activities link aging, telomeres, cortisol and behaviour. It is suggested here that carnosine could provide a therapeutic link between these phenomena because, as noted above, carnosine (i) can act as an anti-aging agent (mimicking rapamycin) including exerting beneficial effects on animal models of age-related brain dysfunction [23][24][25][26][27][28], (ii) can help to maintain telomere length [12], (iii) may enhance cortisol metabolism, at least in mice [36], (iv) ameliorates stress-induced changes in metabolism in restrained mice [37] and (v), when complexed with zinc, suppress the effects of cortisol on rat bone metabolism [38]. Interestingly, it has been suggested that carnosine's anti-stress effects in mice are mediated by modulating the stress-activated hypothalamic-pituitary-adrenal axis [37], whilst it has recently been shown that raised cortisol levels are present in Alzheimer's disease patients' cerebrospinal fluid, possibly arising from dysregulation of the hypothalamic-pituitary-adrenal axis [39].…”

“…Carnosine can inhibit many deleterious biochemical phenomena thought to be associated with generation of the aged phenotype, these include protein damage (including cross-linking [13]) induced by reactive oxygen species [14], reactive nitrogen species [15,16], reducing sugars [13] and reactive carbonyl species such as malondialdehyde [17], 4-hydroxynonenal [18,19] and methylglyoxal [20]. Model animal studies show beneficial effects of the dipeptide towards a number of age-related physiological conditions including impaired wound healing [21,22], Alzheimer's disease [23,24], Parkinson's disease [25,26], stroke [27,28], atherosclerosis [29,30], cataracts [31,32] and diabetic kidney disease [33,34]. In fact it has been claimed that carnosine may be a rapamycin mimetic (a well-recognized anti-aging agent) because many of their respective properties are so similar [35], and recent evidence supports this proposal [10].…”