Neuroprotective effects of carnitinoid compounds in rodent cellular and in vivo models of mitochondrial complex I dysfunction

Rotenone-mediated mitochondrial complex I inhibition was used to model Parkinson’s disease-like syndrome in Lewis rats. Tyrosine hydroxylase immunolabeling demonstrated a decrease in the number of dopaminergic neurons as well as aberrant morphology in surviving neurons. Administration of carnitinoid compounds (synthetic lipoylcarnitine or butyrylcarnitine compounds) reduced dopaminergic neuronal cell loss with characteristic morphology observed in surviving neurons. In a rat primordial hippocampal cell line (H19-7/IGF-IR), rotenone treatment resulted in increased ROS and reduced cellular ATP, while co-treatment with lipoylcarnitine maintained ROS and ATP at control levels. These results illustrate the therapeutic potential of small-molecule carnitinoids in treating neurodegenerative diseases associated with mitochondrial dysfunction.https://mesford.ca/journals/cab/articles-on-biotechnology/neuroprotective-effects-of-carnitinoid-compounds-in-rodent-cellular-and-in-vivo-models-of-mitochondrial-complex-i-dysfunction/Published versio

Klotho pathways, myelination disorders, neurodegenerative diseases, and epigenetic drugs

In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.https://www.liebertpub.com/doi/10.1089/biores.2020.0004Published versio

Carnitinoid lipoic acid derivatives protect photoreceptors after experimental retinal detachment

Purpose: Retinal detachment (RD) is a vision threatening disease that is characterized by the separation of photoreceptors (PR) from the underlying retinal pigment epithelium(RPE). Since photoreceptors have high demand in energy and metabolism, nutrient deprivation after RD can lead to a compromised function of mitochondria and the generation of reactive oxygen species (ROS) in the photoreceptor layer. However, natural antioxidants have concerns of reduced efficacy due to their limited and transient accumulation following oral intake. Thus, we wanted to investigate the effects of mitoprotectant and antioxidant lipoic acid derivatives in experimental RD. Methods: Retinal detachment in mice was induced by subretinal administration of hyalauronic acid 1%. The novel synthetic lipoylcarnitine derivative, lipoyl-L-carnitine methylester iodide (PMX-500FI) was administered intraperitoneally at 40 mg/kg daily. Cyclodextrin was injected as vehicle control. Animals were euthanized at day 1, 3 and 7post RD induction. The effects on PR was examined via TUNEL staining and outer nuclear layer (ONL) thickness evaluation. Inflammatory reaction was evaluated via CD11b staining. Results: PMX-500FI administration led to a significant reduction of TUNEL positive cells in the photo receptor layer compared to vehicle group (p = 0.009) at 24 hours after RD (Fig. 1). Furthermore, a suppression of infiltrating macrophages in the subretinal space 3 days after RD was noted (p = 0.048) (Fig. 2). Administration of PMX-500FI resulted in a substantial preservation of ONL thickness after 7 days of treatment (p = 0.002). Conclusions: These results suggest that bioavailable lipoic acid derivative, PMX-500FI,results in protection of photoreceptors after RD and suggest that lipoic acid derivatives may serve as neuroprotectants.https://iovs.arvojournals.org/article.aspx?articleid=276924

Pathogenic mitochondrial dysfunction and metabolic abnormalities

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.https://doi.org/10.1016/j.bcp.2021.11480

The chemistry of azole sulfides

Note:The chemistry of N, N’-thio and dithiobisimidazole (15, 18), 1, 2, 4-triazole (19, 20), benzimidazole (21. 22), and 1, 2, 3-benzotriazole (23, 24) has been explored. Reactions with N, N’-thiobisbenzimidazole (21) were studied in greater detail. Thus, treating reagent 19 or 21 with dithiols 77 led to oligomeric trisulfides 78 in quantitative yield. Reagent 21 was successfully used in the preparation of 2, 3, 4-benzotrithiepin (87). Biphenyl trisulfide 98 was also prepared but readily desulfurized to disulfide 97. Reagent 21 is reactive towards alcohols and with some benzylic alcohols sulfinate esters (125, 154, 169) and sultines {134, 137, 185, 200, 208) were the products. A stable crystalline cyclic sulfoxylate ester (186) was prepared and shown to be a precursor to sultine 185 and sulfone 186, thus being the first direct example of the involvement of such a species in these rearrangements. [...]La chimie concernant les N, N'-thio et dithiobisimidazo1e (15, 18), 1, 2, 4-triazole (19, 20) benzimidazole (21, 22) et 1, 2, 3-benzotriazole (23, 24) a été explorée. Les réactions mettant en jeu le N, N'-thiobisbenzimidazole ont été étudiées de façon approfondie. De cette manière, faisant réagir les composes 19 et 21 avec des dithiols 77 ceci conduit à la formation d'oligomères trisulfures avec rendement quantitatif. Le réactif a été utilisé avec succès pour la préparation du 2, 3, 4-benzotrithiepin (87). Le trisulfure biphenylique 98 a été également préparé mais subit une désulfurisation rapide pour donner le disulfure 97. Le composé 21 présente une réactivité vis-à-vis les alcools et certains alcools benzyliques pour donner comme produits résultants des esters suffinates (125, 154, 169) et des sultines (134, 137, 185, 200, 208). [...

Butyrate Histone Deacetylase Inhibitors

In addition to being a part of the metabolic fatty acid fuel cycle, butyrate is also capable of inducing growth arrest in a variety of normal cell types and senescence-like phenotypes in gynecological cancer cells, inhibiting DNA synthesis and cell growth in colonic tumor cell lines, suppressing hTERT mRNA expression and telomerase activity in human prostate cancer cells, and inducing stem cell differentiation and apoptosis by DNA fragmentation. It regulates gene expression by inhibiting histone deacetylases (HDACs), enhances memory recovery and formation in mice, stimulates neurogenesis in the ischemic brain, promotes osteoblast formation, selectively blocks cell replication in transformed cells (compared to healthy cells), and can prevent and treat diet-induced obesity and insulin resistance in mouse models of obesity, as well as stimulate fetal hemoglobin expression in individuals with hematologic diseases such as the thalassemias and sickle-cell disease, in addition to a multitude of other biochemical effects in vivo. However, efforts to exploit the potential of butyrate in the clinical treatment of cancer and other medical disorders are thwarted by its poor pharmacological properties (short half-life and first-pass hepatic clearance) and the multigram doses needed to achieve therapeutic concentrations in vivo. Herein, we review some of the methods used to overcome these difficulties with an emphasis on HDAC inhibition

Bioprotective carnitinoids: lipoic acid, butyrate, and mitochondria-targeting to treat radiation injury: mitochondrial drugs come of age

Please note: this work is permanently embargoed in OpenBU. No public access is forecasted for this item. To request private access, please click on the locked Download file link and fill out the appropriate web form.Given nuclear-power-plant incidents such as the 2011 Japanese Fukushima-Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic-driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential–although further research and development is required to prove the effectiveness of this approach–to provide field-ready radiation-protective drugs.The authors thank the MitoCure Foundation for generous support of the underlying experimentation, PhenoMatriX for provision of small molecules, and both the US National Science Foundation and Auburn University for support of original research studies. We acknowledge efforts of Drs. Matthew V. Cannon, Kodeeswaran Parameshwaran, Vishnu Suppiramaniam, David N. Harpp, Edward G. Spack, and Robert J. Zamboni, and the latter for his assistance with the chemical synthesis of PMX-500FI; and Drs. Susan P. Perrine, Michael S. Boosalis, and Jose Sangerman of the Boston University Cancer Research Center for their invaluable advice and helpful discussions in preparation of this manuscript. (US National Science Foundation; Auburn University)Accepted manuscript2031-01-0

D-Galactose Effectiveness in Modeling Aging and Therapeutic Antioxidant Treatment in Mice

Accumulating evidence suggests that mitochondrial dysfunction and oxidative stress play major roles in aging. Chronic administration of D-galactose has been reported to cause deterioration of cognitive and motor skills that are similar to symptoms of aging and, therefore, is regarded as a model of accelerated aging. Because enhancing endogenous antioxidants is now widely regarded as an attractive therapy for conditions associated with mitochondrial oxidative stress, in the present study the effects of α-lipoic acid, L-carnitine, and PMX-500F on D-galactose treated mice were tested. Female mice were injected with (100 mg/kg) D-(+)-galactose for 6 weeks and some groups were treated with a daily dose of α-lipoic acid (5 mg/kg), L-carnitine (3.9 mg/kg), PMX-500F (11.9 mg/kg), or the vehicle (0.1 M Tris, pH 7.4). Control mice were treated with physiological saline. An accelerating Rota-Rod, open field test, and Y-maze test were performed, and serum lactate concentrations were analyzed. These analyses did not identify impairment in motor coordination, open-field activity, or spatial memory (p > 0.05). Similarly, serum lactate concentrations in D-galactose-treated mice were not elevated when compared to controls (p > 0.05). Treatment with the antioxidant compounds at the given concentrations did not result in any changes in the behavioral parameters tested. In conclusion, results of this study illustrate that chronic, short-term D-galactose treatment may not represent a suitable model for inducing readily detectable age-related neurobehavioral symptoms in mice

Microbiota and Neurological Disorders: A Gut Feeling.

In the past century, noncommunicable diseases have surpassed infectious diseases as the principal cause of sickness and death, worldwide. Trillions of commensal microbes live in and on our body, and constitute the human microbiome. The vast majority of these microorganisms are maternally derived and live in the gut, where they perform functions essential to our health and survival, including: digesting food, activating certain drugs, producing short-chain fatty acids (which help to modulate gene expression by inhibiting the deacetylation of histone proteins), generating anti-inflammatory substances, and playing a fundamental role in the induction, training, and function of our immune system. Among the many roles the microbiome ultimately plays, it mitigates against untoward effects from our exposure to the environment by forming a biotic shield between us and the outside world. The importance of physical activity coupled with a balanced and healthy diet in the maintenance of our well-being has been recognized since antiquity. However, it is only recently that characterization of the host-microbiome intermetabolic and crosstalk pathways has come to the forefront in studying therapeutic design. As reviewed in this report, synthetic biology shows potential in developing microorganisms for correcting pathogenic dysbiosis (gut microbiota-host maladaptation), although this has yet to be proven. However, the development and use of small molecule drugs have a long and successful history in the clinic, with small molecule histone deacetylase inhibitors representing one relevant example already approved to treat cancer and other disorders. Moreover, preclinical research suggests that epigenetic treatment of neurological conditions holds significant promise. With the mouth being an extension of the digestive tract, it presents a readily accessible diagnostic site for the early detection of potential unhealthy pathogens resident in the gut. Taken together, the data outlined herein provide an encouraging roadmap toward important new medicines and companion diagnostic platforms in a wide range of therapeutic indications