Neurochemical Damage Research Articles

Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Application of Neck Brace as an Alternative Method of Immobilization after Circular Tracheal Resection. Case Series

Introduction. Cicatricial tracheal stenosis comprises a severe complication of traumatic or prolonged intubation of the trachea. Circular resection of the trachea serves as a radical method of surgical treatment. The distension of the anastamosis can be prevented by immobilization of the neck and head in the thoracic adduction, as a rule, with the Grillo suture technique. This method of fixation creates severe discomfort for the patient, especially when eating. Rare cases involve neurological disorders due to compression of the neurovascular bundles of the neck and spinal cord. Materials and methods. The study enrolled 6 patients diagnosed with cicatricial tracheal stenosis upon admission to the thoracic surgery unit. All patients underwent a circular tracheal resection. Immobilization of the cervical spine was performed using a cervical collar (Schantz collar type). Results. Immobilization was performed within 7–13 days, followed by a control tracheobronchoscopy. No complications related to anastomotic failure and no specific complications when using these orthoses were revealed. Discussion. The postoperative period was reported as uneventful; anastomotic healing proceeded in accordance with the physiological timing indicated by the framework of other studies. The applied orthosis provides immobilization of the cervical spine, preventing from any movement in this area, which is actually similar to the use of the Mulliken-Grillo suture, but has a number of advantages: absence of cosmetic defects, possibility of quick fixation and removal. Significantly, this provides an opportunity to assess the risk of neurochemical damage in patients during preliminary fixation of the head in the hyperflexic position at the preoperative stage. Conclusion. Having such advantages as the absence of cosmetic defects and the possibility of quick removal, this method of neck fixation can be considered as an alternative to the classical fixation method.

Neuroprotective effect of quercetin and nano-quercetin against cyclophosphamide-induced oxidative stress in the rat brain: Role of Nrf2/ HO-1/Keap-1 signaling pathway

Quercetin (Qu) is a powerful flavanol antioxidant that is naturally found in plants and is part of the flavonoid family. Qu has a wide range of biological properties, such as neuroprotective, anti-cancer, anti-diabetic, anti-inflammatory, and radical scavenging capabilities. However, the in vivo application of Qu is limited by its poor water solubility and low bioavailability. These issues could be addressed by utilizing Qu nanoformulations. Cyclophosphamide (CP) is a potent chemotherapeutic agent that causes severe neuronal damage and cognitive impairment due to reactive oxygen species (ROS) overproduction. The present study aimed to explore the proposed neuroprotective mechanism of quercetin (Qu) and quercetin-loaded Chitosan nanoparticles (Qu-Ch NPs) against the brain oxidative damage induced by CP in male albino rats. For this aim, thirty-six adult male rats were randomly divided into six groups (n = 6). Rats were pretreated with Qu and Qu-Ch NPs orally in doses of 10 mg/kg bwt/day for 2 weeks, and CP (75 mg/kg bwt) was administered intraperitoneally 24 h before the termination of the experiment. After 2 weeks, some neurobehavioral parameters were evaluated, and then euthanization was done to collect the brain and blood samples. Results showed that CP induces neurobehavioral deteriorations and impaired brain neurochemical status demonstrated by a significant decrease in brain glutathione (GSH), serum total antioxidant capacity (TAC), and serotonin (5-HT) levels while malondialdehyde (MDA), nitric oxide (NO), Tumor necrosis factor α (TNFα), and choline esterase (ChE) concentrations increased significantly compared to the control group. Pretreatment with Qu and Qu-Ch NPs showed a significant anti-oxidative, anti-depressive, and neuroprotective effect through modification of the above-mentioned parameters. The results were further validated by assessing the expression levels of selected genes in brain homogenates and histopathological investigations were done to pinpoint the exact brain-altered regions. It could be concluded that Qu and Qu-Ch NPs can be useful neuroprotective adjunct therapy to overcome neurochemical damage induced by CP.

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia-Ischemia in the Immature Rat Brain.

Injuries to the developing brain due to hypoxia–ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood–brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf’s promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21–E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin’s neuroprotection capacities and limitation for immature brains.

Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate-glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.

Protective effects of Curcuma longa against neurobehavioral and neurochemical damage caused by cerium chloride in mice.

Cerium chloride (CeCl3) is considered an environmental pollutant and a potent neurotoxic agent. Medicinal plants have many bioactive compounds that provide protection against damage caused by such pollutants. Curcuma longa is a bioactive compound-rich plant with very important antioxidant properties. To study the preventive and healing effects of Curcuma longa on cerium-damaged mouse brains, we intraperitoneally injected cerium chloride (CeCl3, 20mg/kg BW) along with Curcuma longa extract, administrated by gavage (100mg/kg BW), into mice for 60days. We then examined mouse behavior, brain tissue damage, and brain oxidative stress parameters. Our results revealed a significant modification in the behavior of the CeCl3-treated mice. In addition, CeCl3 induced a significant increment in lipid peroxidation, carbonyl protein (PCO), and advanced oxidation protein product levels, as well as a significant reduction in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Acetylcholinesterase (AChE) activity remarkably increased in the brain of CeCl3-treated mice. Histopathological observations confirmed these results. Curcuma longa attenuated CeCl3-induced oxidative stress and increased the activities of antioxidant enzymes. It also decreased AChE activity in the CeCl3-damaged mouse brain that was confirmed by histopathology. In conclusion, this study suggests that Curcuma longa has a neuroprotective effect against CeCl3-induced damage in the brain.

Guanosine Protects Against Traumatic Brain Injury-Induced Functional Impairments and Neuronal Loss by Modulating Excitotoxicity, Mitochondrial Dysfunction, and Inflammation.

Traumatic brain injury (TBI) is one of the most common types of brain injuries that cause death or persistent neurological disturbances in survivors. Most of the promising experimental drugs were not effective in clinical trials; therefore, the development of TBI drugs represents a huge unmet need. Guanosine, an endogenous neuroprotective nucleoside, has not been evaluated in TBI to the best of our knowledge. Therefore, the present study evaluated the effect of guanosine on TBI-induced neurological damage. Our findings showed that a single dose of guanosine (7.5mg/kg, intraperitoneally (i.p.) injected 40min after fluid percussion injury (FPI) in rats protected against locomotor and exploratory impairments 8h after injury. The treatment also protected against neurochemical damage to the ipsilateral cortex, glutamate uptake, Na+/K+-ATPase, glutamine synthetase activity, and alterations in mitochondrial function. The inflammatory response and brain edema were also reduced by this nucleoside. In addition, guanosine protected against neuronal death and caspase 3 activation. Therefore, this study suggests that guanosine plays a neuroprotective role in TBI and can be exploited as a new pharmacological strategy.

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

Assessment of mitochondrial impairment in traumatic brain injury using high-resolution proton magnetic resonance spectroscopy

The goal of this study was to demonstrate the posttraumatic neurochemical damage in normal-appearing brain and to assess mitochondrial dysfunction by measuring N-acetylaspartate (NAA) levels in patients with severe head injuries, using proton (1H) magnetic resonance (MR) spectroscopy. Semiquantitative analysis of NAA relative to creatine-containing compounds (Cr) and choline (Cho) was carried out from proton spectra obtained by means of chemical shift (CS) imaging and single-voxel (SV) methods in 25 patients with severe traumatic brain injuries (TBIs) (Glasgow Coma Scale scores < or = 8) using a 1.5-tesla MR unit. Proton MR spectroscopy was also performed in 5 healthy volunteers (controls). The SV studies in patients with diffuse TBI showed partial reduction of NAA/Cho and NAA/Cr ratios within the first 10 days after injury (means +/- standard deviations 1.59 +/- 0.46 and 1.44 +/- 0.21, respectively, in the patients compared with 2.08 +/- 0.26 and 2.04 +/- 0.31, respectively, in the controls; nonsignificant difference). The ratios gradually declined in all patients as time from injury increased (mean minimum values NAA/Cho 1.05 +/- 0.44 and NAA/Cr 1.05 +/- 0.30, p < 0.03 and p < 0.02, respectively). This reduction was greater in patients with less favorable outcomes. In patients with focal injuries, the periphery of the lesions revealed identical trends of NAA/Cho and NAA/Cr decrease. These reductions correlated with outcome at 6 months (p < 0.01). Assessment with multivoxel methods (CS imaging) demonstrated that, in diffuse injury, NAA levels declined uniformly throughout the brain. At 40 days postinjury, initially low NAA/Cho levels had recovered to near baseline in patients who had good outcomes, whereas no recovery was evident in patients with poor outcomes (p < 0.01). Using (1)H-MR spectroscopy, it is possible to detect the posttraumatic neurochemical damage of the injured brain when conventional neuroimaging techniques reveal no abnormality. Reduction of NAA levels is a dynamic process, evolving over time, decreasing and remaining low throughout the involved tissue in patients with poor outcomes. Recovery of NAA levels in patients with favorable outcomes suggests marginal mitochondrial impairment and possible resynthesis from vital neurons.

Application of chemical shift imaging for measurement of NAA in head injured patients.

Neurochemical damage following brain injury can be assessed non-invasively by measurement of N-Acetyl-Aspartate (NAA) using Proton Magnetic Resonance Spectroscopy (1HMRS). This report documents results of applying Chemical Shift Imaging (CSI) postprocessing for measuring NAA in traumatically injured brain. Following stabilization, severely head-injured patients (GCS 8 or less) were transported to the MRI suite. Semi-quantitative measurement of NAA, creatine (Cr/PCr) and choline (Cho) were obtained from single voxels (8 cm3) and CSI for acquisition of smaller voxels (2 cm3) throughout areas of the brain. Studies were completed with no complication. In focal injury, SVS positioned at the site of lesion demonstrated reduced NAA, compared to contralateral hemisphere. In diffuse injury, CSI demonstrated uniform reduction of NAA throughout the brain. NAA/Cho showed normal levels within 24 hours of injury averaging 2.4 and decreased over the next 10 days reaching a plateau of 0.75. At 30 days, NAA showed no recovery in poor outcome patients. In patients with good outcome, NAA initially low recovered near baseline levels. CSI provides a comprehensive neurochemical assessment of neuronal damage. NAA decreases and remains low in patients with poor outcome. NAA recovers in patients with favorable outcome, suggesting marginal metabolic impairment and possible re-synthesis of the NAA pool.

Return of ATP/PCr and EEG after 75 min of global brain ischemia

Acute, progressive global brain ischemia was induced in awake or anesthetized rats for 5–75 min. Ischemia was achieved with a subclavian-carotid artery occlusion technique (SCOT). After thoracotomy, both subclavian arteries (proximal to their vertebral branches) were tied-off and carotid artery catheter-snares installed. Results show progressive morphological, physiological and neurochemical damage when CBF was reduced from preischemic levels of 115 ml to 0 blood flow. 31P magnetic resonance spectroscopy of high energy phosphate metabolites in vivo showed loss of PCr and β-ATP signals after 6 min brain ischemia. Energy metabolite levels, EEG and CBF normalized within hours after reperfusion. Degree of neuropathologic damage to hippocampal region appeared linearly related to the ischemic duration of ischemia. Thus, acute global brain ischemia resulted in loss of high energy phosphate metabolites, EEG and neuronal integrity in the hippocampal subfields. Reperfusion following short (5 min) or long (75 min) periods of global brain ischemia induced return of 31P-spectra, EEG and CBF to normal but was unable to reverse all of the neuronal damage at the end of the 72-h observation period.

Effects of neonatal monosodium glutamate (MSG) treatment on the hormonal and central monoaminergic dynamics associated with acute ether stress in the male rat

Neonatal treatment with monosodium glutamate (MSG) induces severe neurochemical damage to several brain regions, and these lesions are expressed in adult life by a variety of endocrine and behavioral abnormalities. The present study analyzes the extent of the neurochemical damage to several monoaminergic systems by evaluating the changes in norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) metabolism induced by the neurotoxin in several discrete hypothalamic loci. Moreover, the study also evaluated the ability of MSG-treated rats to respond to acute ether stress, by measuring the release of ACTH and prolactin induced by ether and correlating those changes with the alterations in monoamine metabolism in the arcuate (AN), dorsomedial (DMN), and suprachiasmatic (SCN) nuclei and in the median eminence (ME). The results indicate that MSG treatment induces marked changes in monoamine metabolism in several of the regions examined. The metabolite of DA, dihydroxyphenylacetic acid, was markedly depressed in the AN, SCN, and DMN. NE metabolism was also significantly lower in the AN of MSG-treated animals. 5-HT metabolism was also altered by MSG treatment, with significant decrements recorded in the SCN, DMN, and AN. Both control and MSG-treated rats showed highly significant increments in ACTH and PRL release 5 and 15 min after exposure to ether vapors. The only quantitative difference between the two groups was a smaller increment in ACTH levels 5 min after ether in the MSG group. Ether stress increased DA metabolism in the AN, NE metabolism in the AN and DMN, and 5-HT metabolism in the SCN in control animals. With the exception of the latter, all these changes in amine metabolism were also observed in the MSG rats. In addition, increased NE and DA metabolism was recorded in the SCN and DMN of MSG-treated rats. The results indicate that although MSG treatment causes severe changes in amine metabolism in discrete brain regions, neither the neurochemical nor the hormone response to ether stress appears to be greatly affected. The additional changes in monoamine metabolism observed in MSG rats after ether may represent part of a compensatory mechanism evoked by the central nervous system in adaptation to the neonatally-induced neurochemical deficits.

Exposure to methylmercury [formula omitted][formula omitted]: Effects on biochemical development of catecholamine neurotransmitter systems

Administration of methylmercury to pregnant rats resulted in major alterations in synaptic dynamics of brain dopamine systems in the offspring which were prominent even at doses of the organomercurial which did not produce acute toxicity, fetal or neonatal death, low birth weight or reduced litter sizes. The abnormalities were typified by shortfalls in both the levels and turnover rate of the transmitter in vivo , accompanied by elevations in synaptic uptake as assessed in synaptosomal preparations in vitro . These effects were not apparent in the immediate postnatal period but instead showed a delayed onset beginning at about the time of weaning. Methylmercury exposure displayed selectivity in that central noradrenergic systems showed only the synaptic uptake alterations without changes in transmitter levels or turnover; targeted interactions were also apparent in peripheral sympathetic pathways to the heart and kidney. The threshold dose required to elicit damage to biochemical development of neurotransmitter systems was the same as that to alter more generalized cellular development, as assessed through measurements of brain ornithine decarboxylase activity. These studies indicate that neurochemical damage produced by prenatal exposure of the developing organism to methylmercury involves transmitter-selective alterations in synaptic dynamics and function which may contribute to adverse behavioral outcomes; the underlying mechanisms, however, do not necessarily reflect actions of the organomercurial which are primary or specific to these particular neuronal tissues.

Amygdalar noradrenergic and dopaminergic mechanisms in the regulation of hunger and thirst-motivated behavior

The feeding behavior of rats was studied after neurochemical damage of the amygdalar terminal fields of mesolimbic dopaminergic (DA) and coerular noradrenergic (NA) pathways. 6-Hydroxydopamine (6-OHDA) or 6-hydroxydopa (6-OHDOPA) were injected bilaterally into the central part of amygdala. 6-OHDA was also injected after desmethylimipramine (DMI) pretreatment in order to study the selective destruction of DA terminals. The body weight increased after 6-OHDA injection and a mild hyperphagia and hyperdipsia developed. The 6-OHDA plus DMI treatment resulted in body weight decrease, hypophagia and hypodipsia. These effects were dose-dependent. While a high dose of 6-OHDOPA (15 mug/mul) decreased the body weight, an increase of weight was observed after a low dose (4 mug/0.5 mul). After 6-OHDA, 6-OHDA plus DMI or the high dose of 6-OHDOPA the DA concentration dropped significantly in the amygdala while low-dose 6-OHDOPA resulted in DA increase. In every case there was a parallel change in striatal DA content. The amygdalar NA concentration decreased after both 6-OHDA and the high dose of 6-OHDOPA. There was no change in NA levels after 6-OHDA plus DMI treatment and the NA concentration increased after the injection of a low dose of 6-OHDOPA. When DA/NA ratio was calculated the results showed that body weight increases were accompanied by a relative deficit in NA while a relative deficit of DA was present if body weight decreased. Our results suggest that the amygdalar balance of these transmitters may play an important role in the regulation of body weight and the contradictions of results with electrolytic lesions in the amygdala can be resolved at transmitter level.