Metabolic Brain Disease

Maple syrup urine disease (MSUD) is a metabolic disorder biochemically characterized by the accumulation of branched-chain amino acids (BCAA) and their branched-chain keto acids (BCKA) in blood and tissues. Neurological dysfunction is usually present in the patients, but the pathophysiology of brain damage is still obscure. Considering that brain energy metabolism is possibly altered in MSUD, the main objective of this study was to determine creatine kinase activity in the brain of rats subjected to acute and chronic administration of leucine. Chronic hyperleucinemia was induced by subcutaneous administrations of 4.8 μmol leucine/g body weight, twice a day, from the 6th to the 21st postnatal day. For acute hyperleucinemia, 21-day-old rats received three administrations of the amino acid at 3 h interval. Twelve hours after the chronic treatment or 1 h after the acute one, rats were killed and creatine kinase activity measured. The results indicated that acute or chronic administration of leucine altered creatine kinase activity in the brain of leucine-treated rats. Considering the crucial role creatine kinase plays in energy homeostasis in brain, if these effects also occur in the brain of MSUD patients, it is possible that alteration of this enzyme activity may contribute to the brain damage found in this disease.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative diseases. It is characterized neuropathologically by the presence of alpha-synuclein containing Lewy Bodies in the substantia nigra of the brain with loss of dopaminergic neurons in the pars compacta of the substantia nigra. The presence of alpha-synuclein aggregates in the substantia nigra and the enteric nervous system (ENS) drew attention to the possibility of a correlation between the gut microbiota and Parkinson’s disease. The gut-brain axis is a two-way communication system, which explains how through the vagus nerve, the gut microbiota can affect the central nervous system (CNS), including brain functions related to the ENS, as well as how CNS can alter various gut secretions and immune responses. As a result, this dysbiosis or alteration in gut microbiota can be an early sign of PD with reported changes in short chain fatty acids, bile acids, and lipids. This gave rise to the use of probiotics and faecal microbiota transplantation as alternative approaches to improve the symptoms of patients with PD. The aim of this review is to discuss investigations that have been done to explore the gastrointestinal involvement in Parkinson’s disease, the effect of dysbiosis, and potential therapeutic strategies for PD.

Hyperammonemia is necessary for development of the cerebral complications to liver disease including hepatic encephalopathy and cerebral edema but the mechanisms are unclear. Ammonia is taken up by the brain in proportion to its arterial concentration. The flux into the brain is most likely by both diffusion of NH3 and mediated transport of NH4 + . Astrocytic detoxification of ammonia involves formation of glutamine at concentrations high enough to produce cellular edema, but compensatory mechanisms reduce this effect. Glutamine can be taken up by astrocytic mitochondria and initiate the mitochondrial permeability transition but the clinical relevance is uncertain. Elevated astrocytic glutamine interferes with neurotransmission. Thus, animal studies show enhanced glutamatergic neurotransmission via the NMDA receptor which may be related to the acute cerebral complications to liver failure, while impairment of the NMDA activated glutamate-NO-cGMP pathway could relate to the behavioural changes seen in hepatic encephalopathy. Elevated glutamine also increases GABA-ergic tone, an effect which is aggravated by mitochondrial production of neurosteroids; this may relate to decreased neurotransmission and precipitation of encephalopathy by GABA targeting drugs. Hyperammonemia may compromise cerebral energy metabolism as elevated cerebral lactate is generally reported. Hypoxia is unlikely since cerebral oxygen:glucose utilisation and lactate:pyruvate ratio are both normal in clinical studies. Ammonia inhibits α-ketoglutaratedehydrogenase in isolated mitochondria, but the clinical relevance is dubious due to the observed normal cerebral oxygen:glucose utilization. Recent studies suggest that ammonia stimulates glycolysis in excess of TCA cycle activity, a hypothesis that may warrant further testing, in being in accordance with the limited clinical observations.

Ischemic stroke is one of the most common and undertreated cerebral diseases with high mortality and disability rate. Various intrinsic and extrinsic factors regulate the onset, severity, and progression of ischemic stroke. As an integral part of the neuronal glia system, astrocytes provide many housekeeping functions in nervous system, and perform multiple functions both beneficial and detrimental for neuronal survival after ischemic stroke. In addition, the small GTPase Rho and its downstream Rho kinase (ROCK) are associated with various neuronal functions such as dendrite development, migration and axonal extension, and numerous central nervous system (CNS) diseases. The aim of this review is to summarize the role of RhoA/ROCK signaling pathway and astrocytes on neurological function after ischemic stroke. We also discuss the interaction of RhoA/ROCK signaling pathway and astrocytes on the tissue repair after brain injury.

The regional energy status and the availability of metabolic substrates during brain development are important, since a variety of fetal metabolic insults have been increasingly implicated in the evolution of neonatal brain disorders. The response of the brain to a metabolic insult is determined, in large part, by the ability to utilize the various substrates for intermediary metabolism in order to maintain energy stores within the tissue. To ascertain if metabolic conditions of the fetal brain make it more or less vulnerable to a stress, the high-energy phosphates and glucose-related compounds were examined in five regions of the embryonic day 18 (E-18) fetal brain. Glucose and glycogen levels in the E-18 fetal brain were generally higher in the cerebellum and its neuroepithelium than in the hippocampus, cerebral cortex, and its neuroepithelium. Regional lactate and high-energy phosphate concentrations were essentially the same in the five regions. Subsequently, the metabolic profile was examined in the cerebral cortex and striatum from E-18, postpartum day 7 (P-7) and adult rats. At the various stages of development, there were only minimal differences in the high-energy phosphate levels in the striatum and cortex. Glucose levels, the primary substrate in the adult brain, were essentially unchanged throughout development. In contrast, lactate was significantly elevated by 6- and 2-fold over those in the adult brain in the E-18 and P-7 striatum and cortex, respectively. Another alternative substrate, β-hydroxybutyrate, was also significantly elevated at E-18 and increased more than 2-fold at P-7, but was barely detectable in the adult cortex and striatum. Finally, glucose and lactate levels were examined in cerebrospinal fluid, blood, and brain from the E-18 brain to determine if a gradient among the compartments exists. The levels of both lactate and glucose exhibited a concentration gradient in the E-18 fetus: blood > cerebrospinal fluid > brain parenchyma. The results indicate that energy state in the fetal brain is comparable to that in the neonates and the adults, but that the availability of alternative substrates for intermediary metabolism change markedly with development. The age-dependent substrate specificity for intermediary metabolism could affect the response of the fetal brain to a metabolic insult.

Mucopolysaccharidosis type II (MPS II or Hunter Syndrome) is a lysosomal disease caused by deficient degradation of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate due to the deficiency of the enzyme iduronate-2-sulfatase. The main treatment for MPS II is the administration of the recombinant form of the enzyme, in a process known as enzyme replacement therapy (ERT). Oxidative damage can contribute to the pathophysiology of MPS II and treatment with ERT can reduce the effects of oxidative stress. For a better understanding of pathophysiology of MPS II, we evaluated biomarkers of mitochondrial dysfunction, DNA (Deoxyribonucleic acid) damage, antioxidant defenses, reactive species production and lysosomal size in IDS-deficient HEK 293 cells and investigate the in vitro effect of genistein and coenzyme Q10 (CoQ) on these biomarkers. An increase in the production of reactive species was demonstrated, as well as an increase in the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, an increase in lysosomal volume and oxidative damage to DNA were verified. There was no evidence of a change in mitochondrial function in this cell model. In the HEK 293 (human embryonic kidney 293) knockout (KO) HP10 cell model we found that genistein at concentrations of 25 and 50 μm decreased in vitro the production of reactive species and the activity of the SOD enzyme, showing an antioxidant protective effect. Still, in these cells we verified that the coenzyme Q10 in the concentrations of 5 and 10 μm decreased in vitro the activity of the SOD enzyme and in the concentration of 10 μm decreased in vitro the DNA damage, also demonstrating antioxidant protection. In conclusion, MPS II knockout cells demonstrated oxidative stress and DNA damage and genistein, as well as coenzyme Q10, have been shown to have an important protective effect in vitro against these oxidative damages.

Alzheimer’s disease (AD) is the most common dementia with currently no known cures or disease modifying treatments (DMTs), despite much time and effort from the field. Diagnosis and intervention of AD during the early pre-symptomatic phase of the disease is thought to be a more effective strategy. Therefore, the detection of biomarkers has emerged as a critical tool for monitoring the effect of new AD therapies, as well as identifying patients most likely to respond to treatment. The establishment of the amyloid/tau/neurodegeneration (A/T/N) framework in 2018 has codified the contexts of use of AD biomarkers in neuroimaging and bodily fluids for research and diagnostic purposes. Furthermore, a renewed drive for novel AD biomarkers and innovative methods of detection has emerged with the goals of adding additional insight to disease progression and discovery of new therapeutic targets. The use of biomarkers has accelerated the development of AD drugs and will bring new therapies to patients in need. This review highlights recent methods utilized to diagnose antemortem AD.

Patients with Addison’s disease frequently self-report memory and attention difficulties, even when on standard replacement therapy. However, few published studies examine, using objective measures and assessing across multiple domains, the cognitive functioning of Addison’s disease patients relative to healthy controls. The primary aim of this study was to investigate whether the previously reported subjective cognitive deficits in Addison’s disease are confirmed by objective measures. Conducting comprehensive neuropsychological assessments of patients with relatively rare clinical disorders, such as Addison’s disease, is challenging because access to those patients is often limited, and because their medical condition might prevent extended testing sessions. Brief telephonic cognitive assessments are a useful tool in such circumstances. Hence, we administered the Brief Test of Adult Cognition by Telephone to 27 Addison’s disease patients and 27 matched healthy controls. The instrument provides objective assessment of episodic memory, working memory, executive functioning, reasoning, and speed of processing. Statistical analyses confirmed that, as expected, patients performed significantly more poorly than controls on the episodic memory subtest. There were, however, no significant between-group differences on the attention, executive functioning, reasoning, and speed of processing subtests. Furthermore, patients with a longer duration of illness performed more poorly across all domains of cognition. We conclude that, for Addison’s disease patients, previously reported subjective cognitive deficits are matched by objective impairment, but only in the domain of episodic memory. Future research might investigate (a) whether these memory deficits are material-specific (i.e., whether non-verbal memory is also affected), and (b) the neurobiological mechanisms underlying these deficits.