Ketogenic Diet as a potential treatment for traumatic brain injury in mice.

Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain's resistance to damage and suggest a potential new therapeutic strategy for treating TBI.

Dietary manipulation of vulnerability to traumatic brain injury-induced neuronal plasma membrane permeability.

Traumatic brain injury (TBI) can produce physical disruptions in the plasma membranes of neurons, referred to as mechanoporation, which lead to increased cell permeability. We suspect that such trauma-induced membrane disruptions may be influenced by the physical properties of the plasma membrane, such as elasticity or rigidity. These membrane properties are influenced by lipid composition, which can be modulated via diet, leading to the intriguing possibility of prophylactically altering diet to confer resiliency to this mechanism of acute neuronal damage in TBI. In this proof-of-concept study, we used three different diets-one high in polyunsaturated fatty acids suggested to increase elasticity (Fish Oil), one high in saturated fatty acids and cholesterol suggested to increase rigidity (High Fat), and one standard rat chow (Control)-to alter brain plasma membrane lipid composition before subjecting rats to lateral fluid percussion injury (FPI). Lipid analysis (n = 12 rats) confirmed that diets altered brain fatty acid composition after 4 weeks of feeding, with the Fish Oil diet increasing unsaturated fatty acids, and interestingly, the High Fat diet increasing omega-6 docosapentaenoic acid. One cohort of animals (n = 34 rats) was assessed immediately after FPI or sham injury for acute changes in neuronal membrane permeability in the injury-adjacent cortex. Surprisingly, sham animals fed Fish Oil had increased membrane permeability, suggesting altered passive membrane properties. In contrast, injured animals fed the High Fat diet displayed less intense uptake of permeability marker, suggesting a reduced extent of injury-induced plasma membrane disruption, although the density of affected cells matched the other diet groups. In a separate cohort survived for 7 days after FPI (n = 48 rats), animals fed the High Fat diet exhibited a reduced lesion area. At both time points there were no statistically significant differences in inflammation. Unexpectedly, these results indicate that the High Fat diet, as opposed to the Fish Oil diet, beneficially modulated acute plasma membrane permeability and resulted in a smaller lesion size at 7 days post-injury. Additional studies are necessary to determine the impact of these various diets on behavioral outcomes post-TBI. Further investigation is also needed to understand the physical properties in neuronal plasma membranes that may underlie increased resiliency to trauma-induced disruptions and, importantly, to understand how these properties may be influenced by targeted dietary modifications for vulnerable populations.

A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice.

Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (ß-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.

Nutritional interventions to improve neurophysiological impairments following traumatic brain injury: A systematic review.

Traumatic brain injury (TBI) accounts for significant global health burden. Effects of TBI can become chronic even following mild injury. There is a need to develop effective therapies to attenuate the damaging effects of TBI and improve recovery outcomes. This literature review using a priori criteria (PROSPERO; CRD42018100623) summarized 43 studies between January 1998 and July 2019 that investigated nutritional interventions (NUT) delivered with the objective of altering neurophysiological (NP) outcomes following TBI. Risk of bias was assessed for included studies, and NP outcomes recorded. The systematic search resulted in 43 of 3,748 identified studies met inclusion criteria. No studies evaluated the effect of a NUT on NP outcomes of TBI in humans. Biomarkers of morphological changes and apoptosis, oxidative stress, and plasticity, neurogenesis, and neurotransmission were the most evaluated NP outcomes across the 43 studies that used 2,897 animals. The risk of bias was unclear in all reviewed studies due to poorly detailed methodology sections. Taking these limitations into account, anti-oxidants, branched chain amino acids, and ω-3 polyunsaturated fatty acids have shown the most promising pre-clinical results for altering NP outcomes following TBI. Refinement of pre-clinical methodologies used to evaluate effects of interventions on secondary damage of TBI would improve the likelihood of translation to clinical populations.

Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay.

Traumatic brain injury (TBI) is a global health burden and a major cause of disability and mortality. An early cascade of physical and structural damaging events starts immediately post-TBI. This primary injury event initiates a series of neuropathological molecular and biochemical secondary injury sequelae, that last much longer and involve disruption of cerebral metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and can lead to neuronal damage and death. Coupled to these events, recent studies have shown that lifestyle factors, including diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. There exists molecular cross-talk among the pathways involved in neuronal survival, neuroinflammation, and behavioral outcomes, that are shared among western diet (WD) intake and TBI pathophysiology. As such, poor dietary intake would be expected to exacerbate the secondary damage in TBI. Hence, the aim of this review is to discuss the pathophysiological consequences of WD that can lead to the exacerbation of TBI outcomes. We dissect the role of mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal injury in this context. We show that currently available data conclude that intake of a diet saturated in fats, pre- or post-TBI, aggravates TBI, precludes recovery from brain trauma, and reduces the response to treatment.

Determination of calorie and protein intake among acute and sub-acute traumatic brain injury patients.

PURPOSE: Malnutrition is a common problem among hospitalized patients, especially among traumatic brain injury (TBI) patients. It is developed from hypermetabolism and the condition may worsen under the circumstance of underfeeding or incompatible dietary management. However, the data of nutrient intake especially calorie and protein among TBI patients were scarce. Hence, this study aimed to determine the calorie and protein intake among acute and sub-acute TBI patients receiving medical nutrition therapy in hospital Sultanah Nur Zahirah, Terengganu. METHODS: This observational study involved 50 patients recruited from the neurosurgical ward. Method of 24 h dietary recall was utilized and combined with self-administered food diaries for 2-8 days. Food consumptions including calorie intake and protein intake were analyzed using Nutritionist PRO™ (Woodinville, USA) and manual calculation based on the Malaysian food composition database (2015). RESULTS: Patients consisted of 56% males and 44% females with the median age of 28.0 (IQR = 22.8-36.5) years, of which 92% were diagnosed as mild TBI and the remaining (8%) as moderate TBI. The Glasgow coma scale (GCS) was adopted to classify TBI severity with the score 13-15 being mild and 9-12 being moderate. The median length of hospital stay was 2 (IQR = 2.0-3.3) days. Calorie and protein intake improved significantly from day 1 to discharge day. However, the intake during discharge day was still considered as suboptimal, i.e. 75% of calorie requirement, whilst the median protein intake was only 61.3% relative to protein requirement. Moreover, the average percentages of calorie and protein intakes throughout hospitalization were remarkably lower, i.e. 52.2% and 41.0%, respectively. CONCLUSION: Although the calorie and protein intakes had increased from baseline, hospitalized TBI patients were still at a risk to develop malnutrition as the average intakes were considerably low as compared to their requirements. Optimum nutrient intakes especially calorie and protein are crucial to ensure optimum recovery process as well as to minimize risks of infection and complications.

Role of the ketogenic diet in acute neurological diseases.

The current review outlines the role of ketogenic diet (KD) in the management of acute neurological conditions namely traumatic brain injury, ischemic stroke, status epilepticus and primary aggressive brain tumor. An overview of the scientific literature- both clinical and pre-clinical studies is presented along with the proposed mechanism of ketogenic diet. The review also describes different formulations of commercially available ketogenic diets along with the common adverse effects and dosing recommendations.

Evaluation of the effects of pycnogenol (French maritime pine bark extract) supplementation on inflammatory biomarkers and nutritional and clinical status in traumatic brain injury patients in an intensive care unit: A randomized clinical trial protocol.

BACKGROUND: Traumatic brain injury (TBI) is one of the major health and socioeconomic problems in the world. Immune-enhancing enteral formula has been proven to significantly reduce infection rate in TBI patients. One of the ingredients that can be used in immunonutrition formulas to reduce inflammation and oxidative stress is pycnogenol. OBJECTIVE: The objective of this work is to survey the effect of pycnogenol on the clinical, nutritional, and inflammatory status of TBI patients. METHODS: This is a double-blind, randomized controlled trial. Block randomization will be used. An intervention group will receive pycnogenol supplementation of 150 mg for 10 days and a control group will receive a placebo for the same duration. Inflammatory status (IL-6, IL- 1ß, C-reactive protein) and oxidative stress status (malondialdehyde, total antioxidant capacity), at the baseline, at the 5th day, and at the end of the study (10th day) will be measured. Clinical and nutritional status will be assessed three times during the intervention. The Sequential Organ Failure Assessment (SOFA) questionnaire for assessment of organ failure will be filled out every other day. The mortality rate will be calculated within 28 days of the start of the intervention. Weight, body mass index, and body composition will be measured. All analyses will be conducted by an initially assigned study arm in an intention-to-treat analysis. DISCUSSION: We expect that supplementation of 150 mg pycnogenol for 10 days will improve clinical and nutritional status and reduce the inflammation and oxidative stress of the TBI patients. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (ref: NCT03777683) at 12/13/2018.

Effects of controlled cortical impact and docosahexaenoic acid on rat pup fatty acid profiles.

Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children, particularly in those under four years old. During this period, rapid brain growth demands higher Docosahexaenoic Acid (DHA) intake. DHA is an essential fatty acid and brain cell component derived almost entirely from the diet. DHA improved neurologic outcomes and decreased inflammation after controlled cortical impact (CCI) in 17-day old (P17) rats, our established model of pediatric TBI. In adult rodents, TBI decreases brain DHA. We hypothesized that CCI would decrease rat brain DHA at post injury day (PID) 60, blunted by 0.1% DHA diet. We quantitated fatty acids using Gas Chromatography-Mass Spectrometry. We provided 0.1% DHA before CCI to ensure high DHA in dam milk. We compared brain DHA in rats after 60 days of regular (REG) or DHA diet to SHAM pups on REG diet. Brain DHA decreased in REGCCI, not in DHACCI, relative to SHAMREG. In a subsequent experiment, we gave rat pups DHA or vehicle intraperitoneally after CCI followed by DHA or REG diet for 60 days. REG increased brain Docosapentaenoic Acid (n-6 DPA, a brain DHA deficiency marker) relative to SHAMDHA and DHACCI pups (p < 0.001, diet effect). DHA diet nearly doubled DHA and decreased n-6 DPA in blood but did not increase brain DHA content (p < 0.0001, diet effect). We concluded that CCI or craniotomy alone induces a mild DHA deficit as shown by increased brain DPA.

Early enteral nutrition in patients with severe traumatic brain injury: a propensity score-matched analysis using a nationwide inpatient database in Japan.

BACKGROUND: Whether enteral nutrition (EN) should be administered early in severe traumatic brain injury (TBI) patients has not been fully addressed. OBJECTIVE: The present study aimed to evaluate whether early EN can reduce mortality or nosocomial pneumonia among severe TBI patients. METHODS: Using the Japanese Diagnosis Procedure Combination inpatient database from April 2014 to March 2017 linked with the Survey for Medical Institutions, we identified patients admitted for intracranial injury with Japan Coma Scale scores ≥30 (corresponding to Glasgow Coma Scale scores ≤8) at admission. We designated patients who started EN within 2 d of admission as the early EN group, and those who started EN at 3-5 d after admission as the delayed EN group. The primary outcome was in-hospital mortality. The secondary outcome was nosocomial pneumonia. Propensity score-matched analyses were performed to compare the outcomes between the 2 groups. RESULTS: We identified 3080 eligible patients during the 36-mo study period, comprising 1100 (36%) in the early EN group and 1980 (64%) in the delayed EN group. After propensity score matching, there was no significant difference in in-hospital mortality (difference: -0.3%; 95% CI: -3.7%, 3.1%) between the 2 groups. The proportion of nosocomial pneumonia was significantly lower in the early EN group than in the delayed EN group (difference: -3.2%; 95% CI: -5.9%, -0.4%). CONCLUSIONS: Early EN may not reduce mortality, but may reduce nosocomial pneumonia in patients with severe TBI.

Blueberry Supplementation Mitigates Altered Brain Plasticity and Behavior after Traumatic Brain Injury in Rats.

SCOPE: Traumatic brain injury (TBI) compromises neuronal function required for hippocampal synaptic plasticity and cognitive function. Despite the high consumption of blueberries, information about its effects on brain plasticity and function under conditions of brain trauma is limited. The efficacy of dietary blueberry (BB) supplementation to mitigate the effects of TBI on plasticity markers and associated behavioral function in a rodent model of concussive injury are assessed. METHODS AND RESULTS: Rats were maintained on a diet supplemented with blueberry (BB, 5% w/w) for 2 weeks after TBI. It is found that BB supplementation mitigated a loss of spatial learning and memory performance after TBI, and reduced the effects of TBI on anxiety-like behavior. BB supplementation prevents a reduction of molecules associated with the brain-derived neurotrophic factor (BDNF) system action on learning and memory such as cyclic-AMP response element binding factor (CREB), calcium/calmodulin-dependent protein kinase II (CaMKII). In addition, BB supplementation reverses an increase of the lipid peroxidation byproduct 4-hydroxy-nonenal (4-HNE) after TBI. Importantly, synaptic and neuronal signaling regulators change in proportion with the memory performance, suggesting an association between plasticity markers and behavior. CONCLUSION: Data herein indicate that BB supplementation has a beneficial effect in mitigating the acute aspects of the TBI pathology.

Therapeutic potential of vitamin E and its derivatives in traumatic brain injury-associated dementia.

Traumatic brain injury is one of the most common causes for intervention in neurosurgery. Apart from its acute consequence, it can represent a further burden on individuals as well as society by being associated with significant comorbidity-mainly early-onset dementia. Oxidative stress is one of the crucial mechanisms conferring the damage to nervous tissue, and it is believed it could be, to some extent, influenced by dietary composition, largely by antioxidants contained in the diet. Under stressful conditions, cell-derived reactive oxygen species in the brain can induce the formation of lipid peroxides and the shifting of redox homeostasis. This review discusses the potential of vitamin E as a potent antioxidant and its derived molecules, including vitamin E-based lazaroids, in traumatic brain injury, summarizing the current state of knowledge of its role in TBI-associated dementia.

The ketogenic diet as a treatment for traumatic brain injury: a scoping review.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. The ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after TBI. The purpose of this study is to complete a scoping review and synthesize the evidence regarding the KD and its therapeutic effects in TBI. The methodological framework of Arksey and O'Malley was employed. Databases searched include Medline, EMBASE, CCRCT, CINAHL and WebOfScience. Two reviewers independently screened titles, abstracts and full texts in a two-step screening protocol to determine inclusion. Abstracted data included study setting and therapeutic mechanism. The KD was demonstrated to reduce cerebral oedema, apoptosis, improve cerebral metabolism and behavioural outcomes in rodent TBIs. Additionally, the KD affected rodent TBIs in an age-dependent manner. Due to a lack of relevant outcome measures, the human trials did not establish much evidence with respect to the KD as a treatment for TBI; only its safety was established. The KD is an effective treatment for TBI recovery in rats and shows potential in humans. Future research should aim to better elucidate the KD's mechanisms of action in human TBIs and determine if the KD's effectiveness on clinical outcomes can be reproduced in humans.

Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice.

Study Objectives: In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ-aminobutyric acid (GABA) synthesis, restored impaired sleep-wake regulation and orexin neuronal activity following traumatic brain injury (TBI) in mice. TBI was speculated to reduce orexin neuronal activity through decreased regional excitatory (glutamate) and/or increased inhibitory (GABA) input. Therefore, we hypothesized that TBI would decrease synaptic glutamate and/or increase synaptic GABA in nerve terminals contacting orexin neurons, and BCAA supplementation would restore TBI-induced changes in synaptic glutamate and/or GABA. Methods: Brain tissue was processed for orexin pre-embed diaminobenzidine labeling and glutamate or GABA postembed immunogold labeling. The density of glutamate and GABA immunogold within presynaptic nerve terminals contacting orexin-positive lateral hypothalamic neurons was quantified using electron microscopy in three groups of mice (n = 8 per group): Sham/noninjured controls, TBI without BCAA supplementation, and TBI with BCAA supplementation (given for 5 days, 48 hr post-TBI). Glutamate and GABA were also quantified within the cortical penumbral region (layer VIb) adjacent to the TBI lesion. Results: In the hypothalamus and cortex, TBI decreased relative glutamate density in presynaptic terminals making axodendritic contacts. However, BCAA supplementation only restored relative glutamate density within presynaptic terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions: These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.

Limited effect of omega-3 fatty acids on the quality of life in survivors of traumatic injury: A randomized, placebo-controlled trial.

Empirical evidence is divided on whether n-3 polyunsaturated fatty acid levels are associated with quality of life (QOL). This study investigated the effects of docosahexaenoic acid (DHA) supplementation on QOL in survivors of traumatic injury. In this secondary analysis of a double-blind, randomized controlled trial, we recruited 110 trauma patients (82% men; mean age, 39.6 years) in an intensive care unit. Fifty-three received DHA-rich supplements and 57 received placebo for 12 weeks. We used the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) to assess QOL at the end of intervention. DHA did not significantly affect any QOL domain on the SF-36 after 12 weeks. In the DHA group, changes in the erythrocyte levels of eicosapentaenoic acid (EPA) + DHA and EPA were positively correlated with the SF-36 mental component. DHA did not influence QOL of trauma patients, but increased EPA levels during the trial were associated with better QOL in patients receiving omega-3.

Assessment of a nutritional supplement containing resveratrol, prebiotic fiber, and omega-3 fatty acids for the prevention and treatment of mild traumatic brain injury in rats.

Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. Adolescents are particularly vulnerable and often suffer from post-injury symptomologies that may persist for months. We hypothesized that the combination of resveratrol (RES), prebiotic fiber (PBF), and omega-3 fatty acids (docosahexaenoic acid (DHA)) would be an effective therapeutic supplement for the mitigation of mTBI outcomes in the developing brain. Adolescent male and female Sprague-Dawley rats were randomly assigned to the supplement (3S) or control condition, which was followed by a mTBI or sham insult. A behavioral test battery designed to examine symptomologies commonly associated with mTBI was administered. Following the test battery, tissue was collected from the prefrontal cortex (PFC) and primary auditory cortex for Golgi-Cox analysis of spine density, and for changes in expression of 6 genes (Aqp4, Gfap, Igf1, Nfl, Sirt1, and Tau). 3S treatment altered the behavioral performance of sham animals indicating that dietary manipulations modify premorbid characteristics. 3S treatment prevented injury-related deficits in the longer-term behavior measures, medial prefrontal cortex (mPFC) spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the PFC. Although not fully protective, treatment with the supplement significantly improved post-mTBI function and warrants further investigation.

Effects of immunonutrition on biomarkers in traumatic brain injury patients in Malaysia: a prospective randomized controlled trial.

BACKGROUND: Head injury is one of the top three diagnosis leading to intensive care unit (ICU) admission in Malaysia. There has been growing interest in using immunonutrition as a mode of modulating the inflammatory response to injury or infection with the aim of improving clinical outcome. The aim of the present study was to evaluate the effect of an immunonutrition on biomarkers (IL-6, glutathione, CRP, total protein and albumin) in traumatic brain injury patients. METHODS: Thirty six patients with head injury admitted to neurosurgical ICU in University Malaya Medical Centre were recruited for this study, over a 6-month period from July 2014 to January 2015. Patients were randomized to receive either an immunonutrition (Group A) or a standard (Group B) enteral feed. Levels of biomarkers were measured at day 1, 5 and 7 of enteral feeding. RESULTS: Patients in Group A showed significant reduction of IL-6 at day 5 (p < 0.001) with concurrent rise in glutathione levels (p = 0.049). Patients in Group A also demonstrated a significant increase of total protein level at the end of the study (day 7). CONCLUSION: These findings indicate the potential of immunonutrition reducing cytokines and increasing antioxidant indices in patients with TBI. However, further studies incorporating patient outcomes are needed to determine its overall clinical benefits. TRIAL REGISTRATION: National Medical Research Register (NMRR) ID: 14-1430-23,171. ClinicalTrials.gov identifier: NCT03166449 .

Succinate supplementation improves metabolic performance of mixed glial cell cultures with mitochondrial dysfunction.

Mitochondrial dysfunction, the inability to efficiently utilise metabolic fuels and oxygen, contributes to pathological changes following traumatic spinal cord or traumatic brain injury (TBI). In the present study, we tested the hypothesis that succinate supplementation can improve cellular energy state under metabolically stressed conditions in a robust, reductionist in vitro model of mitochondrial dysfunction in which primary mixed glial cultures (astrocytes, microglia and oligodendrocytes) were exposed to the mitochondrial complex I inhibitor rotenone. Cellular response was determined by measuring intracellular ATP, extracellular metabolites (glucose, lactate, pyruvate), and oxygen consumption rate (OCR). Rotenone produced no significant changes in glial ATP levels. However, it induced metabolic deficits as evidenced by lactate/pyruvate ratio (LPR) elevation (a clinically-established biomarker for poor outcome in TBI) and decrease in OCR. Succinate addition partially ameliorated these metabolic deficits. We conclude that succinate can improve glial oxidative metabolism, consistent our previous findings in TBI patients' brains. The mixed glial cellular model may be useful in developing therapeutic strategies for conditions involving mitochondrial dysfunction, such as TBI.

Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy.

Melatonin functions as a crucial mediator of sterile neuroinflammation; however, the underlying mechanisms remain poorly understood. Dysfunctional mitochondria, a main source of reactive oxygen species, are impacted in inflammation activation. This study aimed to examine the effect of melatonin on inflammation via elimination of damaged mitochondria after controlled cortical impact, an in vivo model of traumatic brain injury (TBI). Here, we demonstrated that inhibition of mitophagy, the selective degradation of damaged mitochondria by autophagy, markedly enhanced inflammation induced by TBI. Melatonin treatment activated mitophagy through the mTOR pathway, then to attenuate TBI-induced inflammation. Furthermore, treatment with melatonin significantly ameliorated neuronal death and behavioral deficits after TBI, while 3-methyladenine reversed this effect by inhibiting mitophagy. Taken together, these results highlight a role for melatonin in protecting against TBI-triggered immunopathology, which is accomplished by negatively regulating inflammation activation and IL-1ß secretion via the autophagy of damaged mitochondria.

Aspectos metabólico-nutricionales en las enfermedades neurológicas / Nutritional and metabolic aspects of neurological diseases

El sistema nervioso central regula la ingesta de nutrientes, la homeostasis de la glucosa y de los electrolitos y pone en marcha las sensaciones de hambre y sed. Diversos factores nutritivos participan en la patogénesis de muchas enfermedades neurológicas. Los pacientes con enfermedades neurológicas agudas (traumatismo craneoencefálico, accidente cerebrovascular hemorrágico o isquémico, lesiones medulares o tumorales) y crónicas (enfermedad de Alzheimer y otras demencias, esclerosis lateral amiotrófica, esclerosis múltiple o enfermedad de Parkinson), incrementan el riesgo de desnutrición por factores múltiples relacionados con ingesta de nutrientes, anormalidades en el gasto energético, trastornos de la conducta alimentaria, cambios gastrointestinales y efectos secundarios de la medicación. Los pacientes con lesión neurológica aguda tienen en común la presencia de un hipermetabolismo e hipercatabolismo que se asocia a un periodo de ayuno prolongado por las frecuentes complicaciones gastrointestinales muchas veces secundarias a los tratamientos administrados. En la fase aguda, las lesiones medulares presentan una reducción del gasto energético asociado a un aumento en la excreción de nitrógeno, para intentar corregir el balance nitrogenado negativo se intente incrementar las ingestas con el resultado de una sobrealimentación que debe evitarse por las complicaciones que comporta. En los pacientes crónicos (y en el ictus en fase aguda) la disfagia es un síntoma que aparece a lo largo de la enfermedad y que condiciona las ingestas. Muchas patologías neurológicas crónicas cursan con demencia que se acompaña de trastornos en la conducta alimentaria. La presencia de desnutrición complica la evolución de estos pacientes, aumenta la atrofia muscular con mayor incidencia de insuficiencia respiratoria y menor capacidad de recuperación de la disfagia, altera el sistema inmunitario con mayor susceptibilidad a infecciones, incrementa la posibilidad de fracturas y de úlceras de presión, aumenta el riesgo de discapacidad y es un factor independiente de mortalidad. No sólo es importante que la valoración nutricional periódica, dadas las múltiples modificaciones a lo largo de su evolución, forme parte de la rutina asistencial de estos pacientes sino deben conocerse las características metabólico-nutricionales observadas en cada situación lo que permitirá prevenir y tratar precozmente las consecuencias clínicas de ello derivadas y así evitar las consecuencias evolutivas de las mismas. Si el soporte nutricional específico está indicado la vía preferencial es la vía digestiva aunque en muchas ocasiones, especialmente en los pacientes críticos, debe optarse por la vía parenteral para asegurar la administración de los nutrientes requeridos (AU)

The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer’s Disease and other dementias, amyotrophic lateral sclerosis, Parkinson’s Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional evaluation due to the evolutionary changes should be part of the treatment. At the same time to know the metabolic and nutritional characteristics is important to be able to prevent and treat early the possible side effects. If nutritional support is indicated, the enteral route is the route of choice although some times, mainly in critical patients, parentral nutrition is necessary to ensure the administration of the required nutrients (AU)