Carbonic anhydrase activity in the frontal lobe of human brain.

Carbonic anhydrase (CA) plays an important role in many biological processes. Recent technological advances have demonstrated the feasibility of measuring CA activity in the occipital lobe of human subjects in vivo. In this work we report, for the first time, in vivo measurement of CA activity in the frontal lobe of human brain, where structural and function abnormalities are strongly associated with symptoms of major psychiatric disorders. Despite the much larger magnetic field distortion in the frontal lobe, the pseudo first-order bicarbonate dehydration rate constant was determined with high precision using in vivo 13 C magnetic resonance magnetization transfer spectroscopy following oral administration of [U-13 C6 ]glucose. Nuclear Overhauser effect pulses were used to increase the signal-to-noise ratio; no proton decoupling was applied. The unidirectional dehydration rate constant of bicarbonate was found to be 0.26 ± 0.07 s-1 , which is not statistically different from the dehydration rate constant in the occipital lobe determined in our previous study, indicating that CA activity in the two brain regions is essentially indistinguishable. These results demonstrate the feasibility of characterizing CA activity in the frontal lobe for future psychiatric studies.

Synthetic ß-hydroxy ketone derivative inhibits cholinesterases, rescues oxidative stress and ameliorates cognitive deficits in 5XFAD mice model of AD.

Alzheimer's disease (AD) is a progressive, chronic and age-related neurodegenerative disorder that affects millions of people across the world. In pursuit of new anti-AD remedies, 2-[Hydroxy-(4-nitrophenyl)methyl]-cyclopentanone (NMC), a ß hydroxyl ketone derivative was studied to explore its neuroprotective potentials against AD. The in-vitro AChE and BuChE enzymes inhibition were evaluated by Ellman protocol and antioxidant potentials of NMC by DPPH free radical scavenging assay. In-vivo behavioral studies were performed in the transgenic 5xFAD mice model of AD using shallow water maze (SWM), Paddling Y-Maze (PYM), elevated plus maze (EPM) and balance beam (BB) tests. Also, the ex-vivo cholinesterase inhibitory effects of NMC and histopathological analysis of amyloid-ß plaques were determined in the frontal cortex and hippocampal regions of the mice brain. NMC exhibited significant in vitro anti-cholinesterase enzyme potentials with an IC50 value of 67 µg/ml against AChE and 96 µg/ml against BuChE respectively. Interestingly, the activities of AChE and BuChE enzymes were also significantly lower in the cortex and hippocampus of NMC-treated groups. Also, in the DPPH assessment, NMC displayed substantial antioxidant properties with an IC50 value observed as 171 µg/ml. Moreover, histopathological analysis via thioflavin-s staining displayed significantly lower plaques depositions in the cortex and hippocampus region of NMC-treated mice groups. Furthermore, SWM, PYM, EPM, and BB behavioral analysis indicated that NMC enhanced spatial learning, memory consolidation and improved balance performance. Altogether, to the best of our knowledge, we believe that NMC may serve as a potential and promising anti-cholinesterase, antioxidant and neuroprotective agent against AD.

Controlled ozone therapy modulates the neurodegenerative changes in the frontal cortex of the aged albino rat.

Aging is a normal process associated with neurodegenerative changes resulting in decline of cognitive and motor functions. Oxidative stress plays an important role. Controlled ozone (O3) therapy has been proved to induce oxidative preconditioning thus reversing oxidative stress. To the best of our knowledge, this research is the first attempt to investigate whether the antioxidant properties of O3 can ameliorate age-associated structural alterations of the cerebral cortex. Ozone administration (at a dose of 0.7mg/kg intraperitonially, three times a week for eight weeks) produced significant downregulation of tissue malondialdehyde (MDA) and upregulation of glutathione, superoxide dismutase (SOD) and catalase (CAT) within the frontal cortex of aged rats. Sections of the frontal cortex from adult and aged rats were stained with hematoxylin and eosin and analyzed using light microscopy. In addition, quantitative immunohistochemical assessments of the expression of inducible nitric oxide synthase (iNOS), caspase-3, glial fibrillary acidic protein (GFAP), Ki67 and acetylcholinesterase (AChE) were performed. Our results revealed the beneficial effect of O3 in improving the neurodegenerative changes of the cerebral cortex of aged rats. Moreover, this study clarified that O3 exerted its effects via reducing oxidative stress, apoptosis, gliosis as well as improving neurogenesis and cholinergic plasticity. This work added to the previously proved aging - associated neurodegenerative effects and provided a new insight into the promising role of O3 to ameliorate these effects.

Functional and neurometabolic asymmetry in SHR and WKY rats following vasoactive treatments.

A lateralized distribution of neuropeptidase activities in the frontal cortex of normotensive and hypertensive rats has been described depending on the use of some vasoactive drugs and linked to certain mood disorders. Asymmetrical neuroperipheral connections involving neuropeptidases from the left or right hemisphere and aminopeptidases from the heart or plasma have been suggested to play a role in this asymmetry. We hypothesize that such asymmetries could be extended to the connection between the brain and physiologic parameters and metabolic factors from plasma and urine. To assess this hypothesis, we analyzed the possible correlation between neuropeptidases from the left and right frontal cortex with peripheral parameters in normotensive (Wistar Kyoto [WKY]) rats and hypertensive rats (spontaneously hypertensive rats [SHR]) untreated or treated with vasoactive drugs such as captopril, propranolol and L-nitro-arginine methyl ester. Neuropeptidase activities from the frontal cortex were analyzed fluorometrically using arylamide derivatives as substrates. Physiological parameters and metabolic factors from plasma and urine were determined using routine laboratory techniques. Vasoactive drug treatments differentially modified the asymmetrical neuroperipheral pattern by changing the predominance of the correlations between peripheral parameters and central neuropeptidase activities of the left and right frontal cortex. The response pattern also differed between SHR and WKY rats. These results support an asymmetric integrative function of the organism and suggest the possibility of a different neurometabolic response coupled to particular mood disorders, depending on the selected vasoactive drug.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.

Synaptic ATPases system of rat frontal cerebral cortex during aging.

Energy metabolism is fundamental to maintain Central Nervous System homeostasis because of high requirement of adenosine triphosphate (ATP), that is necessary to sustain neuronal events. During aging, changes in brain bioenergetics may influence the recovery of cerebral tissue in coping with pathophysiological conditions and pharmacological treatments. For this reason, we have previously studied enzyme catalytic activities related to energy-yielding systems. In the present study, the maximum rates (Vmax) of some enzymatic activities related to energy consumption (ATPases) were evaluated on synaptic plasma membranes (S.P.M.) isolated from frontal cerebral cortex of male Wistar rats aged 2, 6, 12, 18 and 24 months, because of the key role of these enzymes in modulating presynaptic nerve ending homeostasis. The following enzyme activities were evaluated: Na+, K+, Mg2+-ATPase; ouabain-insensitive Mg2+-ATPase; Na+, K+-ATPase; specific Mg2+-ATPase; Ca2+, Mg2+-ATPase; acetylcholinesterase (AChE). The present results show that both the activities of (i) ATPases and (ii) AChE were significantly decreased during aging. Comparing these observations with those previously done on rat striatum on the same functional parameters and in the same experimental settings, ATPases activities were influenced by the age factor in different ways, suggesting that the frontal cerebral cortex independently adapt to the different age-dependent biochemical situations at each single age. Overall, this experimental approach is therefore important to add pieces of information for the understanding of the correlation between aging and brain energy metabolism, and could be a suitable model to assess also drug effects, differentiating between different cerebral areas.

Neuropeptidase activity in the frontal cortex of Wistar-Kyoto and spontaneously hypertensive rats treated with vasoactive drugs: a bilateral study.

BACKGROUND AND OBJECTIVE: Hypertension can lead to mood disorders that may worsen or ameliorate depending on the type of antihypertensive prescribed. Depression is associated with modifications in basal brain asymmetry particularly that of the frontal cortex, which is involved in blood pressure control. Furthermore, different vasoactive drugs may change the brain's asymmetry in a manner that contributes to cognition status. We studied the bilateral activity of several neuropeptidases in frontal cortex as a reflect of the functional status of certain neuropeptides involved in mood. METHODS: Using arylamide derivatives as substrates, we fluorometrically analysed the activity of these enzymes in the left and right frontal cortex of control untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs) and compared their activities with WKY or SHR treated with the antihypertensive drugs captopril (CAP) and propranolol (PRO) or with the hypertensive N (G)-nitro-L-arginine methyl ester. SBP was also measured in all WKY and SHR groups. RESULTS: Untreated WKY, WKY treated with CAP or PRO and SHR treated with CAP exhibited normotensive values of SBP. However, WKY treated with N (G)-nitro-L-arginine methyl ester as well as untreated SHR and SHR treated with PRO and N(G)-nitro-L-arginine methyl ester demonstrated hypertensive values of SBP. Changes in the bilateral distribution of neuropeptidases were depending on the strain, the enzyme analysed and the drug used. Normotensive WKY groups (WKY, CAP, PRO) revealed intrahemispheric correlations mainly in the left hemisphere. In contrast, WKY treated with N(G)-nitro-L-arginine methyl ester and SHR groups demonstrated intrahemispheric correlations mainly in the right hemisphere. Interhemispheric correlations were mostly observed in WKY as well as in SHR groups with antihypertensive treatments (CAP, PRO). CONCLUSION: Our results suggest specific brain bilateral patterns of neuropeptidase activities in WKY that change in SHR. This observation may be related to the cognitive disorders that have been described in these animals and that change under antihypertensive or hypertensive drug's treatments.

Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats.

Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase (AChE) activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors was also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased thiobarbituric acid reactive substances (TBARS) in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition.

Stachys sieboldii Extract Supplementation Attenuates Memory Deficits by Modulating BDNF-CREB and Its Downstream Molecules, in Animal Models of Memory Impairment.

Cholinergic dysfunction, impaired brain-derived neurotrophic factor and cAMP response element binding protein (BDNF-CREB) signaling are one of the major pathological hallmarks of cognitive impairment. Therefore, improving cholinergic neurotransmission, and regulating the BDNF-CREB pathway by downregulating apoptosis genes is one strategy for inhibiting the etiology of dementia. This study evaluates the potential effects of Stachys sieboldii MIQ (SS) extract against cognitive dysfunction and its underlying mechanisms. SS supplementation for 33 days improved scopolamine-induced memory impairment symptoms in Morris water maze test and Y-maze test. SS reduced the acetylcholineesterase activity and significantly increase acetylcholine and cholineacetyltransferase activity in the brain. In the subsequent mechanism study, SS regulated the mRNA expression level of neuronal plasticity molecules such as (nerve growth factor) NGF, BDNF, CREB, and its downstream molecules such as Bcl-2 and Egr-1 by downregulating the neuronal apoptosis targets in both hippocampus and frontal cortex. Additionally, inward currents caused by SS in hippocampal CA1 neurons was partially blocked by the GABA receptor antagonist picrotoxin (50 µM), suggesting that SS acts on synaptic/extrasynaptic GABAA receptors. These findings indicate that SS may function in a way that is similar to nootropic drugs by inhibiting cholinergic abnormalities, and neuronal apoptosis targets and ultimately increasing the expression of BDNF-CREB.

Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice.

Mammalian asparagine endopeptidase (AEP) is a lysosomal cysteine protease that cleaves protein substrates on the C-terminal side of asparagine. The expression and activity of AEP are closely related to many pathological conditions that include cancer, atherosclerosis and inflammation. It has been validated that the level of AEP is elevated in aged human and neurodegenerative diseases like Alzheimer's disease (AD). Mood disorder is one of the most emotional symptoms that can be seen in AD patients, which leads us to assume that AEP can modulate affective behaviors. AEP knockout (AEP KO) and wildtype (WT) mice were used in this study, and a series of behavioral tests were performed to establish a potential link between AEP and psychiatric disorders. It was demonstrated that AEP KO mice displayed lower anxiety-like behavior and more advance exploratory behavior in open-field and hole-board tests. AEP KO mice reduced depressive-like behaviors in the forced swim and tail suspension tests. Morris water maze (MWM) test showed that the abilities of spatial learning and memory were elevated in AEP-deletion mice compared with those of WT mice. Furthermore, the enhanced synaptic plasticity (LTP and DPT) as well as the increased expressions of SYP and PSD-95 proteins in hippocampus were showed in AEP KO mice. Otherwise, the level of BDNF protein was reduced and the level of NF-κB p65 protein was increased in hippocampus and frontal cortex of AEP KO mice. These data highlight the importance of studying AEP in the anxiety and depression behaviors and the spatial learning and memory.

Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.

BACKGROUND: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism. OBJECTIVE: We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. METHODS: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks. Ethanol-fed rats were binge-administered ethanol (2 g/kg; on Mondays, Wednesdays, and Fridays) by intraperitoneal (i.p.) injection, while control group administered saline in weeks 7 and 8 (n=12/group). Six rats from each group were administered i.p. injections of NNK (2 mg/kg) or saline on Tuesdays, Thursdays, and Saturdays of weeks 3 through 8. Alcohol dehydrogenase, catalase, and aldehyde dehydrogenase activities were measured using commercial assays. Cytochrome P450 mRNA levels (17 isoforms) were measured by quantitative reverse transcription-polymerase chain reaction. Malondialdehyde immunoreactivity was measured by enzyme-linked immunosorbent assay. RESULTS: Dual exposures to ethanol and NNK significantly increased frontal lobe ADH activity relative to control (P=0.01) and ethanol only (P=0.04) treatments, and ALDH relative to control (P=0.02). In contrast, malondialdehyde-protein expression was not significantly altered by ethanol+NNK. Ethanol decreased CYP1A1 mRNA expression relative to control (P=0.02), and combined ethanol+NNK exposures decreased the expression of CYP1A1 (P=0.01) and CYP2C6 (P=0.03). CONCLUSION: Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism.

Dietary Zinc Modulates Matrix Metalloproteinases in Traumatic Brain Injury.

Animal models of mild traumatic brain injury (mTBI) provide opportunity to examine the extent to which dietary interventions can be used to improve recovery after injury. Animal studies also suggest that matrix metalloproteinases (MMPs) play a role in tissue remodeling post-TBI. Because dietary zinc (Zn) improved recovery in nonblast mTBI models, and the MMPs are Zn-requiring enzymes, we evaluated the effects of low- (LoZn) and adequate-Zn (AdZn) diets on MMP expression and behavioral responses, subsequent to exposure to a single blast. MMP messenger RNA expression in soleus muscle and frontal cortex tissues were quantified at 48 h and 14 days post-blast. In muscle, blast resulted in significant upregulation of membrane-type (MT)-MMP, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 at 48 h post-injury in rats consuming AdZn. At 14 days post-blast, there were no blast or dietary effects observed on MMP levels in muscle, supporting the existence of a Zn-responsive, functional repair and remodeling mechanism. In contrast, blast resulted in a significant downregulation of MT-MMP, TIMP-1, and TIMP-2 and a significant upregulation of MMP-3 levels at 48 h post-injury in cortex tissue, whereas at 14 days post-blast, MT-MMP, MMP-2, and TIMP-2 were all downregulated in response to blast, independent of diet, and TIMP-1 were significantly increased in rats fed AdZn diets despite the absence of elevated MMPs. Because the blast injuries occurred while animals were under general anesthesia, the increased immobility observed post-injury in rats consuming LoZn diets suggest that blast mTBI can, in the absence of any psychological stressor, induce post-traumatic stress disorder-related traits that are chronic, but responsive to diet. Taken together, our results support a relationship between marginally Zn-deficient status and a compromised regenerative response post-injury in muscle, likely through the MMP pathway. However, in neuronal tissue, changes in MMP/TIMP levels after blast indicate a variable response to marginally Zn-deficient diets that may help explain compromised repair mechanism(s) previously associated with the systemic hypozincemia that develops in patients with TBI.

Changes in Activity of Cysteine Cathepsins B and L in Brain Structures of Mice with Aggressive and Depressive-Like Behavior Formed under Conditions of Social Stress.

We studied activity of lysosomal cysteine proteases, cathepsins B and L, in brain structures (frontal cortex, caudate nucleus, hippocampus, and hypothalamus) of C57Bl/6J mice with aggressive and depressive-like behavior formed under conditions of chronic social stress (repeated experience of victories and defeats within 20 days). Mice with depressive-like behavior showed increased activity of cathepsin В in the hypothalamus and nucleus caudatus and increased activity of cathepsin L in the hippocampus compared to control animals not subjected to agonistic confrontations. In mice with aggressive behavior, protease activity in the studied brain structures was not changed. In 4 h after immune system activation with LPS (250 µg/kg), cathepsin L activity in the hippocampus of control mice increased in comparison with mice receiving saline. In contrast to control animals, LPS caused a decrease in activity of the enzyme in the caudate nucleus and frontal cortex of aggressive mice and in the hippocampus of mice with depressive-like behavior.

Purine-related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer's disease pathology.

Adenosine, hypoxanthine, xanthine, guanosine and inosine levels were assessed by HPLC, and the activity of related enzymes 5'-nucleotidase (5'-NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) measured in frontal (FC), parietal (PC) and temporal (TC) cortices at different stages of disease progression in Alzheimer's disease (AD) and in age-matched controls. Significantly decreased levels of adenosine, guanosine, hypoxanthine and xanthine, and apparently less inosine, are found in FC from the early stages of AD; PC and TC show an opposing pattern, as adenosine, guanosine and inosine are significantly increased at least at determinate stages of AD whereas hypoxanthine and xanthine levels remain unaltered. 5'-NT is reduced in membranes and cytosol in FC mainly at early stages but not in PC, and only at advanced stages in cytosol in TC. ADA activity is decreased in AD when considered as a whole but increased at early stages in TC. Finally, PNP activity is increased only in TC at early stages. Purine metabolism alterations occur at early stages of AD independently of neurofibrillary tangles and ß-amyloid plaques. Alterations are stage dependent and region dependent, the latter showing opposite patterns in FC compared with PC and TC. Adenosine is the most affected of the assessed purines.

Treatment of obstructive sleep apnoea-hypopnea syndrome by mandible advanced device reduced neuron apoptosis in frontal cortex of rabbits.

Objective: To investigate effects of mandible advanced device (MAD) therapy for obstructive sleep apnoea-hypopnea syndrome (OSAHS) on the neuron apoptosis and acetylcholine esterase activity in frontal cortex. Materials and methods: Thirty male New Zealand white rabbits were randomly divided into three groups (n = 10 in each group): group OSAHS, group MAD, and control group. Hydrophilic polyacrylamide gel was injected into soft palate of the animals to induce OSAHS in group OSAHS and group MAD. The group MAD animals wore MAD to relief the obstructiveness. The control group was not given any treatment. Computed tomography (CT) examination of the upper airway and polysomnography (PSG) recordings were performed in supine position. All rabbits were induced to sleep in a supine position for 4 to 6 hours every day and were observed for consecutive 8 weeks. The frontal cortices of three groups were dissected and the neuron apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry. Acetylcholine esterase (AchE) activity in the frontal cortex was measured by spectrophotometry. Results: The group OSAHS exhibited high neuron apoptosis rate and low AchE activity than those of group MAD and control group. The blood oxygen saturation was negatively correlated with neuronal apoptosis rate and positively correlated with AchE activity. Applying MAD in OSAHS animals significantly improve the neuronal damage and function deficits by apnoea-hypoxia caused by narrowed upper airway. Conclusion: This study provided evidence that MAD therapy for OSAHS can significantly decrease neuronal apoptosis and increase AchE activity in the frontal cortex.

[Mexidol effect on the factor induced by hypoxia HIF-1α expression in the rat cerebral cortex in ischemia]. / Vliianie meksidola na ékspressiiu faktora, indutsiruemogo gipoksiei HIF-1α, v kore bol'shikh polusharii golovnogo mozga krys pri ishemii.

The aim of the research - to study the Mexidol (ethylmethylhydroxypyridine succinate) effect on the factor induced by hypoxia (HIF-1α) expression in the frontal cortex of the brain in its ischemia. MATERIAL AND METHODS: The work was performed on the 64 male Wistar rats. The expression of HIF-1α was determined immunohistochemically. RESULTS AND DISCUSSION: It is determined that single intraperitoneal administration of Mexidol at a dose 120 mg/kg and oral administration at a dose 100 mg/kg three times a day for 14 days is not affected the expression of HIF-1α. Unilateral occlusion of the common carotid artery increases the expression of HIF-1α at 4 hours after the occlusion. Oral administration of Mexidol at a dose 100 mg/kg three times a day for 14 days before and after ischemia increases the expression of HIF-1α after 4 and 12 hours in comparison with the norm, on the 5th day in comparison with occlusion control. Thus, it has been established that Mexidol increases the expression of HIF-1α in the frontal cortex of rat brain not under normal conditions, but in unilateral occlusion of the common carotid artery.

Temporal changes of oxidative stress markers in Escherichia coli K1-induced experimental meningitis in a neonatal rat model.

Despite advances in antimicrobial therapy and advanced critical care neonatal bacterial meningitis has a mortality rate of over 10% and induces neurological sequelae in 20-50% of cases. Escherichia coli K1 (E. coli K1) is the most common gram-negative organism causing neonatal meningitis and is the second most common cause behind group B streptococcus. We previously reported that an E. coli K1 experimental meningitis infection in neonatal rats resulted in habituation and aversive memory impairment and a significant increase in cytokine levels in adulthood. In this present study, we investigated the oxidative stress profile including malondialdehyde (MDA) levels, carbonyl protein formation, myeloperoxidase activity (MPO) activity, superoxide dismutase (SOD) activity and catalase (CAT) activity 6, 12, 24, 48, 72 and 96h after E. coli K1 experimental meningitis infection. In addition, sulfhydryl groups, nitrite and nitrate levels and activity of the mitochondrial respiratory chain enzymes were also measured in the frontal cortex and hippocampus of neonatal rats. The results from this study demonstrated a significant increase in MDA, protein carbonyls and MPO activity and a simultaneous decrease in SOD activity in the hippocampus of the neonatal meningitis survivors but the same was not observed in frontal cortex. In addition, we also observed a significant increase in complex IV activity in the hippocampus and frontal cortex of meningitis survivor rats. Thus, the results from this study reaffirmed the possible role of oxidative stress, nitric oxide and its related compounds in the complex pathophysiology of E. coli K1-induced bacterial meningitis.

Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer's disease.

Defects in p21-activated kinase (PAK) lead to dendritic spine abnormalities and are sufficient to cause cognition impairment. The decrease in PAK in the brain of Alzheimer's disease (AD) patients is suspected to underlie synaptic and dendritic disturbances associated with its clinical expression, particularly with symptoms related to frontal cortex dysfunction. To investigate the role of PAK combined with Aß and tau pathologies (3xTg-AD mice) in the frontal cortex, we generated a transgenic model of AD with a deficit in PAK activity (3xTg-AD-dnPAK mice). PAK inactivation had no effect on Aß40 and Aß42 levels, but increased the phosphorylation ratio of tau in detergent-insoluble protein fractions in the frontal cortex of 18-month-old heterozygous 3xTg-AD mice. Morphometric analyses of layer II/III pyramidal neurons in the frontal cortex showed that 3xTg-AD-dnPAK neurons exhibited significant dendritic attrition, lower spine density and longer spines compared to NonTg and 3xTg-AD mice. Finally, behavioral assessments revealed that 3xTg-AD-dnPAK mice exhibited pronounced anxious traits and disturbances in social behaviors, reminiscent of fronto-dependent symptoms observed in AD. Our results substantiate a critical role for PAK in the genesis of neuronal abnormalities in the frontal cortex underlying the emergence of psychiatric-like symptoms in AD.

Monoamine oxidase-A and B activities in the cerebellum and frontal cortex of children and young adults with autism.

Monoamine oxidases (MAOs) catalyze the metabolism of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, and are key regulators for brain function. In this study, we analyzed the activities of MAO-A and MAO-B in the cerebellum and frontal cortex from subjects with autism and age-matched control subjects. In the cerebellum, MAO-A activity in subjects with autism (aged 4-38 years) was significantly lower by 20.6% than in controls. When the subjects were divided into children (aged 4-12 years) and young adults (aged 13-38 years) subgroups, a significant decrease by 27.8% in the MAO-A activity was observed only in children with autism compared with controls. When the 95% confidence interval of the control group was taken as a reference range, reduced activity of MAO-A was observed in 70% of children with autism. In the frontal cortex, MAO-A activity in children with autism was also lower by 30% than in the control group, and impaired activity of MAO-A was observed in 55.6% of children with autism, although the difference between the autism and control groups was not significant when all subjects were considered. On the contrary, there was no significant difference in MAO-B activity in both the cerebellum and frontal cortex between children with autism and the control group as well as in adults. These results suggest impaired MAO-A activity in the brain of subjects with autism, especially in children with autism. Decreased activity of MAOs may lead to increased levels of monoaminergic neurotransmitters, such as serotonin, which have been suggested to have a critical role in autism. © 2017 Wiley Periodicals, Inc.

GSK3ß 5'-flanking DNA Methylation and Expression in Alzheimer's Disease Patients.

BACKGROUND: The GSK3ß has been associated to pathological functions in neurodegenerative diseases. This kinase is involved in hyperphosphorylation of microtubule-associated tau protein, leading to aggregation andformation of NFTs. It has clearly been shown that GSK3ß is regulated at posttranslational level: phosphorylation at Tyr216 activates kinase, while phosphorylation at Ser9 is essential to inhibit its activity. OBJECTIVES: At present, there are contradictory findings about the possibility that GSK3ß may be regulated at gene level. Previous data showed overexpression of GSK3ß mRNA in hypomethylating conditions, pointing out to the existence of epigenetic mechanisms responsible for GSK3ß gene regulation. Analysis of human GSK3ß promoter through bisulphite modification, both in neuroblastoma cells and in postmortem frontal cortex from AD patients (AD patients both at Braak stages I-II and at stages V-VI) , allowed us to characterize the methylation pattern of a putative CpG islands in human GSK3ß 5'- flanking region. RESULTS: The analysis evidenced overall hypomethylation of CpG and non-CpG cytosine residues both in cells and in human brain (AD patients and control subjects). We found that GSK3ß mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3ß in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. CONCLUSIONS: These results point out that GSK3ß hyperactivity, and then NFTs formation, could come into function at an early stage of the disease and then turn off at the last stages.