Effect of acute and long-term administration of gold nanoparticles on biochemical parameters in rat brain.

The present study investigated stress oxidative parameters and activities of enzymes of the energy metabolism in various brain structures. Rats were subjected to acute and long-term administration of gold nanoparticles (GNPs) with mean diameters of 10nm and 30nm. Adult (60days old) male Wistar rats received a single intraperitoneal injection (acute administration; 70µg·kg-1) or repeated injections once daily for 28days (long-term administration; 70µg·kg-1) of saline solution or GNPs (10nm or 30nm). Twenty-four hours after administration of the final dose, the animals were killed and the cerebral structures were isolated for enzyme analysis. In this study, we observed that the thiobarbituric acid-reactive species and carbonyl protein levels were decreased after acute administration of GNPs, whereas the superoxide dismutase activity was increased after acute and long-term of GNPs. The catalase activity was affected by the administration of GNPs. Furthermore, we have not found change in the citrate synthase activity. The succinate dehydrogenase, malate dehydrogenase, complexes I, II, II-III and IV, and creatine kinase activities were altered. These results indicate that inhibition energy metabolism can be caused by oxidative stress.

Gold nanoparticles prevent cognitive deficits, oxidative stress and inflammation in a rat model of sporadic dementia of Alzheimer's type.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia in the aged brain. Even though its etiology is unknown, factors such as neuroinflammation, mitochondrial dysfunction, formation of reactive oxygen species (ROS), and impaired insulin signaling may play a role. We used a sporadic AD model in rats generated by intracerebroventricular-streptozotocin (i.c.v.-STZ) injection to test the therapeutic effect of gold nanoparticles (GNPs). We tested the null hypothesis that there would be no difference between the STZ+GNPs group and the STZ group in the analyzed markers. We observed that STZ-induced impairment in mitochondrial ATP production, neuroinflammation, and oxidative stress were all prevented by GNP treatment. Moreover, while STZ induced deficits in both spatial and recognition memory, GNPs prevented this effect. These results suggest that GNPs may be considered as a potential treatment for dementias.

Effects of primaquine and chloroquine on oxidative stress parameters in rats.

Primaquine and chloroquine are used for the treatment of malaria; evidence from the literature suggests that these drugs may induce oxidative stress. In this study we investigated the effects of primaquine and chloroquine on oxidative damage and DNA damage in brain, liver and kidney of rats after 7, 14 and 21 days of administration. Our results demonstrated that primaquine causes DNA damage in brain after 7, 14 and 21 days, and in liver after 7 and 14 days. Moreover, primaquine increases TBARS levels in the kidney and protein carbonyls in the brain after 14 days, and decreases protein carbonyls in the liver after 7 days. Whereas chloroquine causes DNA damage in the kidney after 7 and 14 days, and in the liver after 14 and 21 days, increases TBARS levels in the kidney after 7 days, and decreases TBARS levels in the brain after 21 days. Moreover, decreases protein carbonyls in the liver after 7 and 14 days, and in the brain after 7 and 21 days. However, chloroquine treatment for 14 days increases protein carbonyls in the brain and kidney. In conclusion, these results showed that prolonged treatment with antimalarial may adversely affect the DNA.

Acute administration of fenproporex increased acetylcholinesterase activity in brain of young rats.

Fenproporex is the second most commonly amphetamine-based anorectic consumed worldwide; this drug is rapidly converted into amphetamine, in vivo, and acts by increasing dopamine levels in the synaptic cleft. Considering that fenproporex effects on the central nervous system are still poorly known and that acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine, the present study investigated the effects of acute administration of fenproporex on acetylcholinesterase activity in brain of young rats. Young male Wistar rats received a single injection of fenproporex (6.25, 12.5 or 25mg/kg i.p.) or vehicle (2% Tween 80). Two hours after the injection, the rats were killed by decapitation and the brain was removed for evaluation of acetylcholinesterase activity. Results showed that fenproporex administration increased acetylcholinesterase activity in the hippocampus and posterior cortex, whereas in the prefrontal cortex, striatum and cerebellum the enzyme activity was not altered. In conclusion, in the present study we demonstrated that acute administration of fenproporex exerts an effect in the cholinergic system causing an increase in the activity of acetylcholinesterase in a dose-dependent manner in the hippocampus and posterior cortex. Thus, we suggest that the imbalance in cholinergic homeostasis could be considered as an important pathophysiological mechanism underlying the brain damage observed in patients who use amphetamines such as fenproporex.

Gold nanoparticles and/or N-acetylcysteine mediate carrageenan-induced inflammation and oxidative stress in a concentration-dependent manner.

We report the effect of gold nanoparticles (AuNP) in an acute inflammation model induced by carrageenan (CG) and compared this effect with those induced by the antioxidant N-acetylcysteine (NAC) alone and by the synergistic effect of NAC and AuNP together. Male Wistar rats received saline or saline containing CG administered into the pleural cavity, and some rats also received NAC (20 mg/kg) subcutaneously and/or AuNP administered into the pleural cavity immediately after surgery. Four hours later, the rats were sacrificed and pleural exudates obtained for evaluation of cytokine levels and myeloperoxidase activities. Oxidative stress parameters were also evaluated in the lungs. The results demonstrated that the inflammatory process caused by the administration of CG into the pleural cavity resulted in a substantial increase in the levels of tumor necrosis factor-α, interleukin-1ß, and myeloperoxidase and a reduction in interleukin-10 levels. These levels seem to be reversed after different treatments in animals. Antioxidant enzymes exhibited positive responses after treatment of NAC + AuNP, and all treatments were effective at reducing lipid peroxidation and oxidation of thiol groups induced by CG. These findings suggest that small compounds, such as NAC plus AuNP, may be useful in the treatment of conditions associated with local inflammation.

Lithium increases leukocyte mitochondrial complex I activity in bipolar disorder during depressive episodes.

RATIONALE: Different lines of evidence suggest that mitochondrial dysfunction may be implicated in bipolar disorder (BD) pathophysiology. Mitochondrial electron transport chain (ETC) is a key target to evaluate mitochondrial function, but its activity has never been assessed in unmedicated BD or during mood episodes. Also, lithium has been shown to increase ETC gene expression/activity in preclinical models and in postmortem brains of BD subjects, but to date, no study has evaluated lithium's direct effects on ETC activity in vivo. OBJECTIVES: This study aims to evaluate leukocyte ETC complexes I-IV activities in acute depressive episode in BD (compared to controls) and the effect of lithium treatment on ETC activity. METHODS: Subjects with short-term BD during a depressive episode (n=25) were treated for 6 weeks with lithium. Leukocytes were collected at baseline and endpoint and mitochondrial ETC complexes I-IV activities were evaluated and compared to age-matched healthy controls (n=24). RESULTS: Lithium significantly increased mitochondrial complex I activity from baseline to endpoint (p=0.02), with no changes in other complexes after 6 weeks. Also, plasma lithium levels were significantly correlated to mitochondrial complex I activity after treatment (p=0.003). Mitochondrial complexes I-IV activities did not differ during depressive episodes in BD compared to healthy controls. CONCLUSIONS: Our findings demonstrate for the first time an increase in mitochondrial ETC complex I activity in vivo after lithium treatment in BD, which was positively associated with plasma lithium levels. Further studies are warranted to clarify the potential role of this target in neuroprotection-related drug development.

Inflammatory cytokines content in Achilles tendinopathy after phonophoresis treatment combined with gold nanoparticles and diclophenac diethylammonium in rats.

Tendinitis is a painful condition that occurs in tendons in response to repetitive use or direct trauma. The therapeutic approaches commonly employed to modulate inflammation have not achieved complete success in chronic cases of tendinitis. In this scenario, considering the anti-inflammatory properties of pulsed therapeutic ultrasound and gold nanoparticles (GNPs), this study assesses the possible therapeutic effects of phonophoresis in association with diclophenac diethylammonium and GNPs by measuring the inflammatory parameters interleukin 1ß and tumor necrosis factor alpha in acute tendinous injury. Wistar rats were randomly divided into three groups and were treated with phonophoresis and diclophenac diethylammonium, GNP gel, and a combination thereof. A significant decrease in interleukin 1ß and tumor necrosis factor alpha occurred in tendons treated with phonophoresis+diclophenac+GNPs. The content of both cytokines were similar after combined treatment with phonophoresis+diclophenac+GNPs. Apart from the anti-inflammatory effect, GNPs transported and enhanced drug action when used with phonophoresis.

The characterization of neuroenergetic effects of chronic L-tyrosine administration in young rats: evidence for striatal susceptibility.

Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in hepatic cytosolic aminotransferase. Affected patients usually present a variable degree of mental retardation, which may be related to the level of plasma tyrosine. In the present study we evaluated effect of chronic administration of L-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes I, II, II-III and IV in cerebral cortex, hippocampus and striatum of rats in development. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); rats were killed 12 h after last injection. Our results demonstrated that L-tyrosine inhibited the activity of citrate synthase in the hippocampus and striatum, malate dehydrogenase activity was increased in striatum and succinate dehydrogenase, complexes I and II-III activities were inhibited in striatum. However, complex IV activity was increased in hippocampus and inhibited in striatum. By these findings, we suggest that repeated administrations of L-tyrosine cause alterations in energy metabolism, which may be similar to the acute administration in brain of infant rats. Taking together the present findings and evidence from the literature, we hypothesize that energy metabolism impairment could be considered an important pathophysiological mechanism underlying the brain damage observed in patients with tyrosinemia type II.

Fluvoxamine alters the activity of energy metabolism enzymes in the brain

Objective: Several studies support the hypothesis that metabolism impairment is involved in the pathophysiology of depression and that some antidepressants act by modulating brain energy metabolism. Thus, we evaluated the activity of Krebs cycle enzymes, the mitochondrial respiratory chain, and creatine kinase in the brain of rats subjected to prolonged administration of fluvoxamine. Methods: Wistar rats received daily administration of fluvoxamine in saline (10, 30, and 60 mg/kg) for 14 days. Twelve hours after the last administration, rats were killed by decapitation and the prefrontal cortex, cerebral cortex, hippocampus, striatum, and cerebellum were rapidly isolated. Results: The activities of citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV were decreased after prolonged administration of fluvoxamine in rats. However, the activities of complex II, succinate dehydrogenase, and creatine kinase were increased. Conclusions: Alterations in activity of energy metabolism enzymes were observed in most brain areas analyzed. Thus, we suggest that the decrease in citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV can be related to adverse effects of pharmacotherapy, but long-term molecular adaptations cannot be ruled out. In addition, we demonstrated that these changes varied according to brain structure or biochemical analysis and were not dose-dependent. .

Methylphenidate treatment causes oxidative stress and alters energetic metabolism in an animal model of attention-deficit hyperactivity disorder.

OBJECTIVES: To evaluate oxidative damage through the thiobarbituric acid-reactive species (TBARS) and protein carbonyl groups; antioxidant enzymatic system - superoxide dismutase (SOD) and catalase (CAT); and energetic metabolism in the brain of spontaneously hypertensive adult rats (SHR) after both acute and chronic treatment with methylphenidate hydrochloride (MPH). METHODS: Adult (60 days old) SHRs were treated during 28 days (chronic treatment), or 1 day (acute treatment). The rats received one i.p. injection per day of either saline or MPH (2 mg/kg). Two hours after the last injection, oxidative damage parameters and energetic metabolism in the cerebellum, prefrontal cortex, hippocampus, striatum and cortex were evaluated. RESULTS: We observed that both acute and/or chronic treatment increased TBARS and carbonyl groups, and decreased SOD and CAT activities in many of the brain structures evaluated. Regarding the energetic metabolism evaluation, the acute and chronic treatment altered the energetic metabolism in many of the brain structures evaluated. CONCLUSION: We observed that both acute and chronic use of methylphenidate hydrochloride (MPH) in adult spontaneously hypertensive rats (SHRs) was associated with increased oxidative stress and energetic metabolism alterations. These data also reinforce the importance of the SHR animal model in further studies regarding MPH.

Evaluation of Na+, K+-ATPase activity in the brain of young rats after acute administration of fenproporex

Objectives: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. Methods: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. Results: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. Conclusion: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability. .

Fluvoxamine alters the activity of energy metabolism enzymes in the brain.

OBJECTIVE: Several studies support the hypothesis that metabolism impairment is involved in the pathophysiology of depression and that some antidepressants act by modulating brain energy metabolism. Thus, we evaluated the activity of Krebs cycle enzymes, the mitochondrial respiratory chain, and creatine kinase in the brain of rats subjected to prolonged administration of fluvoxamine. METHODS: Wistar rats received daily administration of fluvoxamine in saline (10, 30, and 60 mg/kg) for 14 days. Twelve hours after the last administration, rats were killed by decapitation and the prefrontal cortex, cerebral cortex, hippocampus, striatum, and cerebellum were rapidly isolated. RESULTS: The activities of citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV were decreased after prolonged administration of fluvoxamine in rats. However, the activities of complex II, succinate dehydrogenase, and creatine kinase were increased. CONCLUSIONS: Alterations in activity of energy metabolism enzymes were observed in most brain areas analyzed. Thus, we suggest that the decrease in citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV can be related to adverse effects of pharmacotherapy, but long-term molecular adaptations cannot be ruled out. In addition, we demonstrated that these changes varied according to brain structure or biochemical analysis and were not dose-dependent.

Omega-3 fatty acids alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidences indicate that omega-3 (ω3) fatty acids play several important roles in brain development and functioning. Moreover, preclinical and clinical evidence suggests roles for ω3 fatty acids in BD. Considering these evidences, the present study aimed to investigate the effects of ω3 fatty acids on locomotor behavior and oxidative stress parameters (TBARS and protein carbonyl content) in brain of rats subjected to an animal model of mania induced by fenproporex. The fenproporex treatment increased locomotor behavior in saline-treated rats under reversion and prevention model, and ω3 fatty acids prevented fenproporex-related hyperactivity. Moreover, fenproporex increased protein carbonyls in the prefrontal cortex and cerebral cortex, and the administration of ω3 fatty acids reversed this effect. Lipid peroxidation products also are increased in prefrontal cortex, striatum, hippocampus and cerebral after fenproporex administration, but ω3 fatty acids reversed this damage only in the hippocampus. On the other hand, in the prevention model, fenproporex increased carbonyl content only in the cerebral cortex, and administration of ω3 fatty acids prevented this damage. Additionally, the administration of fenproporex resulted in a marked increased of TBARS in the prefrontal cortex, hippocampus, striatum and cerebral cortex, and prevent this damage in the prefrontal cortex, hippocampus and striatum. In conclusion, we are able to demonstrate that fenproporex-induced hyperlocomotion and damage through oxidative stress were prevented by ω3 fatty acids. Thus, the ω3 fatty acids may be important adjuvant therapy of bipolar disorder.

Il1-ß involvement in cognitive impairment after sepsis.

Sepsis is defined as the host's reaction to infection and characterised by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters, apoptosis and cognitive impairment. It's known that the IL-1ß is one of the first cytokines to be altered. Thus, the objective of this study was to evaluate the role of IL-1ß in cognitive parameters in brain tissue through the use of an IL-1ß (IL-1ra) receptor antagonist up to 10 days and to assess blood-brain barrier permeability, cytokine levels, oxidative parameters and energetic metabolism up to 24 h, after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation (CLP) procedure. Immediately after, the animals received one dose of 10 µg of IL-1ra. After 24 h, the rats were killed and were evaluated for biochemical parameters in the pre-frontal cortex, hippocampus and striatum. After 10 days, the animals were submitted to the habituation to the open field and step-down inhibitory avoidance task. We observed that the use of IL-1ra reverted the increase of blood-brain barrier permeability in the pre-frontal cortex, hippocampus and striatum; the increase of IL-1ß, IL1-6 and TNF-α levels in the pre-frontal cortex and striatum; the decrease of complex I activity in the pre-frontal, hippocampus and striatum; the increase of oxidative parameters in pre-frontal cortex, hippocampus and striatum; and cognitive impairment. In conclusion, the results observed in this study reinforce the role of acute brain inflammatory response, in particular, the IL1ß response, in the cognitive impairment associated with sepsis.

L-tyrosine induces DNA damage in brain and blood of rats.

Mutations in the tyrosine aminotransferase gene have been identified to cause tyrosinemia type II which is inherited in an autosomal recessive manner. Studies have demonstrated that an excessive production of ROS can lead to reactions with macromolecules, such as DNA, lipids, and proteins. Considering that the L-tyrosine may promote oxidative stress, the main objective of this study was to investigate the in vivo effects of L-tyrosine on DNA damage determined by the alkaline comet assay, in brain and blood of rats. In our acute protocol, Wistar rats (30 days old) were killed 1 h after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. For chronic administration, the animals received two subcutaneous injections of L-tyrosine (500 mg/kg, 12-h intervals) or saline administered for 24 days starting at postnatal day (PD) 7 (last injection at PD 31), 12 h after the last injection, the animals were killed by decapitation. We observed that acute administration of L-tyrosine increased DNA damage frequency and damage index in cerebral cortex and blood when compared to control group. Moreover, we observed that chronic administration of L-tyrosine increased DNA damage frequency and damage index in hippocampus, striatum, cerebral cortex and blood when compared to control group. In conclusion, the present work demonstrated that DNA damage can be encountered in brain from animal models of hypertyrosinemia, DNA alterations may represent a further means to explain neurological dysfunction in this inherited metabolic disorder and to reinforce the role of oxidative stress in the pathophysiology of tyrosinemia type II.

Fenproporex increases locomotor activity and alters energy metabolism, and mood stabilizers reverse these changes: a proposal for a new animal model of mania.

Fenproporex (Fen) is converted in vivo into amphetamine, which is used to induce mania-like behaviors in animals. In the present study, we intend to present a new animal model of mania. In order to prove through face, construct, and predictive validities, we evaluated behavioral parameters (locomotor activity, stereotypy activity, and fecal boli amount) and brain energy metabolism (enzymes citrate synthase; malate dehydrogenase; succinate dehydrogenase; complexes I, II, II-III, and IV of the mitochondrial respiratory chain; and creatine kinase) in rats submitted to acute and chronic administration of fenproporex, treated with lithium (Li) and valproate (VPA). The administration of Fen increased locomotor activity and decreased the activity of Krebs cycle enzymes, mitochondrial respiratory chain complexes, and creatine kinase, in most brain structures evaluated. In addition, treatment with mood stabilizers prevented and reversed this effect. Our results are consistent with the literature that demonstrates behavioral changes and mitochondrial dysfunction caused by psychostimulants. These findings suggest that chronic administration of Fen may be a potential animal model of mania.

Evaluation of Na+, K+-ATPase activity in the brain of young rats after acute administration of fenproporex.

OBJECTIVES: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. METHODS: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. RESULTS: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. CONCLUSION: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability.

An evaluation of the effects of acute and chronic L-tyrosine administration on BDNF levels and BDNF mRNA expression in the rat brain.

Tyrosinemia type II, which is also known as Richner-Hanhart syndrome, is an inborn error of metabolism that is due to a block in the transamination reaction that converts tyrosine to p-hydroxyphenylpyruvate. Because the mechanisms of neurological dysfunction in hypertyrosinemic patients are poorly known and the symptoms of these patients are related to the central nervous system, the present study evaluated brain-derived neurotrophic factor (BDNF) levels and bdnf mRNA expression in young rats and during growth. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old), and the rats were killed 12 h after the last injection. The brains were rapidly removed, and we evaluated the BDNF levels and bdnf mRNA expression. The present results showed that the acute administration of L-tyrosine decreased both BDNF and bdnf mRNA levels in the striatum of 10-day-old rats. In the 30-day-old rats, we observed decreased BDNF levels without modifications in bdnf transcript level in the hippocampus and striatum. Chronic administration of L-tyrosine increased the BDNF levels in the striatum of rats during their growth, whereas bdnf mRNA expression was not altered. We hypothesize that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. The present results enhance our knowledge of the pathophysiology of hypertyrosinemia.

Effect of acute administration of L-tyrosine on oxidative stress parameters in brain of young rats.

Tyrosinemia type II, also known as Richner-Hanhart syndrome, is an autosomal recessive inborn error of metabolism caused by a deficiency of hepatic cytosolic tyrosine aminotransferase, and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that studies demonstrated that high concentrations of tyrosine provoke oxidative stress in vitro and in vivo in the cerebral cortex of rats, in the present study we investigate the oxidative stress parameters (enzymatic antioxidant defenses, thiobarbituric acid-reactive substances and protein carbonyl content) in cerebellum, hippocampus and striatum of 30-old-day rats after acute administration of L-tyrosine. Our results demonstrated that the acute administration of L-tyrosine increased the thiobarbituric acid reactive species levels in hippocampus and the carbonyl levels in cerebellum, hippocampus and striatum. In addition, acute administration of L-tyrosine significantly decreased superoxide dismutase activity in cerebellum, hippocampus and striatum, while catalase was increased in striatum. In conclusion, the oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia and the administration of antioxidants may be considered as a potential adjuvant therapy for tyrosinemia, especially type II.

Effect of acute and chronic administration of L-tyrosine on nerve growth factor levels in rat brain.

Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Neurological manifestations are variable and some patients are developmentally normal, while others show different degrees of developmental retardation. Considering that current data do not eliminate the possibility that elevated levels of tyrosine and/or its derivatives may have noxious effects on central nervous system development in some patients, the present study evaluated nerve growth factor (NGF) levels in hippocampus, striatum and posterior cortex of young rats. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal administration of L-tyrosine (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); the rats were killed 12 h after the last injection. NGF levels were then evaluated. Our findings showed that acute administration of L-tyrosine decreased NGF levels in striatum of 10-day-old rats. In the 30-day-old rats, NGF levels were decreased in hippocampus and posterior cortex. On the other hand, chronic administration of L-tyrosine increased NGF levels in posterior cortex. Decreased NGF may impair growth, differentiation, survival and maintenance of neurons.