Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease.

In addition to classic motor symptoms, Parkinson's disease (PD) is characterized by cognitive and emotional deficits, which have been demonstrated to precede motor impairments. The present study addresses the question of whether a partial degeneration of dopaminergic neurons using 6-hydroxydopamine (6-OHDA) in rats is able to induce premotor behavioral signs. The time-course of nigrostriatal damage was evaluated by tyrosine hydroxylase immunohistochemistry and the levels of dopamine, noradrenaline, and 5-HT in various brain regions were analyzed by high performance liquid chromatography (HPLC). Behavioral tests that assessed a variety of psychological functions, including locomotor activity, emotional reactivity and depression, anxiety and memory were conducted on 6-OHDA lesioned rats. Bilateral infusion of 6-OHDA in the striatum of rats caused early (1 week) damage of dopaminergic terminals in striatum and in cell bodies in substantia nigra pars compacta. The nigrostriatal lesion was accompanied by early loss of dopamine in the striatum, which remained stable through a 3-week period of observation. In addition, a late (3 weeks) loss of dopamine in the prefrontal cortex, but not in the hippocampus, was seen. Additional noradrenergic and serotonergic alterations were observed after 6-OHDA administration. The results indicated that 6-OHDA lesioned rats show decreased sucrose consumption and an increased immobility time in the forced swimming test, an anhedonic-depressive-like effect. In addition, an anxiogenic-like activity in the elevated plus maze test and cognitive impairments were observed on the cued version of the Morris water maze and social recognition tests. These findings suggest that partial striatal dopaminergic degeneration and parallel dopaminergic, noradrenergic and serotonergic alterations in striatum and prefrontal cortex may have caused the emotional and cognitive deficits observed in this rat model of early phase PD.

Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease.

There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg) and xylazine (3 mg/kg) (K/X) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease. The bilateral infusion of MPTP (100 microg/side) or 6-OHDA (10 microg/side) into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67%) or severe (~91%) loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33% of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51% due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP- and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.

Conductance fluctuations in high mobility monolayer graphene: Nonergodicity, lack of determinism and chaotic behavior.

We have fabricated a high mobility device, composed of a monolayer graphene flake sandwiched between two sheets of hexagonal boron nitride. Conductance fluctuations as functions of a back gate voltage and magnetic field were obtained to check for ergodicity. Non-linear dynamics concepts were used to study the nature of these fluctuations. The distribution of eigenvalues was estimated from the conductance fluctuations with Gaussian kernels and it indicates that the carrier motion is chaotic at low temperatures. We argue that a two-phase dynamical fluid model best describes the transport in this system and can be used to explain the violation of the so-called ergodic hypothesis found in graphene.

The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson's disease.

Depression is one of the most common psychiatric symptoms in patients with Parkinson's disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

Benzodiazepines in the brain. Their origin and possible biological roles.

Great progress has been made in the last 5 yr in demonstrating the presence of benzodiazepines (BDZs) in mammalian tissues, in beginning studies on the origin of these natural compounds, and in elucidating their possible biological roles. Many unanswered questions remain regarding the sources and biosynthetic pathways responsible for the presence of BDZs in brain and their different physiological and/or biochemical actions. This essay will focus on recent findings supporting that: (1) BDZs are of natural origin; (2) mammalian brain contains BDZs in concentrations ranging between 5 x 10(-10)-10(-8) M; (3) dietary source of BDZs might be a plausible explanation for their occurrence in animal tissues, including man; (4) the formation of BDZ-like molecules in brain is a possibility, experimentally supported; (5) BDZ-like molecules including diazepam and N-desmethyldiazepam are elevated in hepatic encephalopathy; and (6) natural BDZs in the brain are involved in the modulation of memory processes. Future studies using the full range of biochemical, physiological, behavioral, and molecular biological techniques available to the neuroscientist will hopefully continue to yield exciting and new information concerning the biological roles that BDZs might play in the normal and pathological functioning of the brain.

Primary renal aspergillosis: extremely uncommon presentation in patients treated with bone marrow transplantation.

Invasive aspergillosis affects 3 to 11% of BMT patients with a high mortality rate (60 to 95%). Extra-pulmonary disease is an unusual event, and primary renal aspergillosis is extremely uncommon. A patient with CML treated with BMT, who developed primary renal and subsequently hepatic aspergillosis, is described. Dysfunction of the mucosal barrier secondary to conditioning therapy, was a possible portal of entry for the fungus. Fine needle aspiration was very useful, as is direct microscopic examination of the urine, for diagnosis of the fungal infection. Surgical drainage of the abscess followed by antifungal therapy is the treatment of choice. Unconducive situations, such as refractory thrombocytopenia, are associated with the worst outcome in these patients.

Early gram-positive bacteremia in BMT recipients: impact of three different approaches to antimicrobial prophylaxis.

Antimicrobial prophylaxis against gram-positive bacteremia (GPB) following BMT may prevent infections but promote antimicrobial resistance. In a sequential cohort study involving 289 consecutive BMT recipients we compared three protocols for prevention of GPB (vancomycin prophylaxis, penicillin/cefazolin prophylaxis, and no specific GPB prophylaxis) with respect to incidence of GPB, mortality, and vancomycin use. GPB was associated with increased mortality (27% vs 15%; P = 0.02), but contributed to only five of 52 deaths in the study population, and only one of 15 subjects with viridans streptococcal bacteremia developed fatal septic shock. Vancomycin prophylaxis reduced the incidence of GPB (11%) compared to penicillin/cefazolin (27%) or no prophylaxis (40%) (all P < 0.03), but did not significantly reduce mortality. The incidence of fungemia, gram-negative bacteremia, and infection-associated mortality was unaffected by GPB prophylaxis. Vancomycin use was substantially greater in the vancomycin prophylaxis group. We conclude that in comparison with vancomycin prophylaxis, BMT support regimens that do not include vancomycin prophylaxis allow reduced overall vancomycin use without an apparent increase in early post-BMT mortality, despite the greater associated frequency of GPB.

Naltrexone potentiates the anxiolytic effects of chlordiazepoxide in rats exposed to novel environments.

RATIONALE: Both novelty and naloxone have been reported to modify the anxiolytic-like effect of benzodiazepines in the elevated plus maze. In addition, it has been largely demonstrated that novelty alters endogenous opioid activity. OBJECTIVES: The present study was designed to examine a possible interaction between novelty and naltrexone effects on the behavior of chlordiazepoxide-treated rats in two animal models of anxiety. METHODS: Thirty minutes after acute intraperitoneal treatment with saline or naltrexone and saline or chlordiazepoxide, male Wistar rats were exposed for the first time to the elevated plus maze apparatus or the social interaction arena for the quantification of the percentage of time spent in the open arms or the time of active social interaction, respectively. The effects of naltrexone and/or chlordiazepoxide on the plus maze and the social interaction tests were also evaluated after previous exposure to the respective apparatus. RESULTS: Naltrexone dose dependently increased the percentage of time spent in the open arms of the elevated plus maze in chlordiazepoxide-treated (5 mg/kg i.p.) rats exposed for the first time to the apparatus. Similarly, naltrexone (5 mg/kg i.p.) increased the time spent in active social interaction by chlordiazepoxide-treated rats exposed to an unfamiliar arena. In both experiments, naltrexone had no effect when administered alone. When both the plus maze and the social interaction tests were conducted after previous exposure to the respective apparatus, naltrexone did not modify the behavior of chlordiazepoxide- or saline-treated rats. CONCLUSIONS: These data suggest that the anxiolytic-like effects of chlordiazepoxide can be modified by opioid mechanisms in novel environments.

Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia.

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

Habituation and inhibitory avoidance training alter brain regional levels of benzodiazepine-like molecules and are affected by intracerebral flumazenil microinjection.

The effects of habituation and inhibitory avoidance training on the rat brain regional levels of benzodiazepine (BZD)-like molecules and on central type BZD binding sites were examined. BZD-like immunoreactivity was decreased by 26-50% in the amygdala, cerebral cortex and septum of rats sacrificed immediately after stepping-down from the platform of an inhibitory avoidance apparatus (non-trained group) as compared to naive controls. Rats submitted to a second step-down session 20 h later (habituated group) have significantly lower BZD-like immunoreactivity in the septum (-60%) as compared to non-trained animals. Rats exposed to an inhibitory avoidance training, i.e. stepping-down and receiving a footshock (trained group), showed a significant reduction in the content of BZD-like molecules in cerebral cortex (-44%), amygdala (-68%), septum (-80%) and hippocampus (-82%) as compared to non-trained rats. In addition, the density of central type BZD binding sites was slightly increased in the hippocampus and septum of trained rats. No changes were observed in the apparent dissociation constant. No changes were observed in parallel measurements of [3H]-L-quinuclidinyl benzylate binding constants at cholinergic muscarinic binding sites. The immediate posttraining intrahippocampal bilateral injection of the central type BZD receptor antagonist flumazenil (10 nmol/hippocampus), enhanced the retention of habituation but not when injected in the amygdala or septum. In contrast, retention of the inhibitory avoidance task was significantly increased by flumazenil administered bilaterally into any of the 3 brain structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Memory facilitation by post-training intraperitoneal, intracerebroventricular and intra-amygdala injection of Ro 5-4864.

Post-training i.p. (2.0 or 5.0 mg/kg), i.c.v. (2.5 micrograms/rat), or intra-amygdala (1.6-40 ng/amygdala) administration of Ro 5-4864 causes memory facilitation of step-down inhibitory avoidance in rats. The effect is expressed as an increased latency to step down in a retention test carried out 24 h after training. Ro 5-4864 is a blocker of the Cl(-)-channel associated with GABAA receptors, at a site sensitive to the antagonist, PK11195, and different from that sensitive to picrotoxin. PK11195, given i.c.v. (2.5 micrograms/rat) or into the amygdala (8 ng/amygdala), antagonized the effect of Ro 5-4864. Intra-amygdala picrotoxin administration (80 ng/amygdala) also caused retrograde memory facilitation, but its effect was not antagonized by PK11195. At a higher dose (40 ng/amygdala), PK11195 had an amnestic effect of its own, which suggests that it might be acting against an endogenous ligand of receptor to Ro 5-4864 in the Cl(-)-channel. These findings support the hypothesis that there is a GABAA mechanism in the amygdala normally involved in the modulation of the post-training memory processing of aversive learnings.

Phosphatidylserine reverses reserpine-induced amnesia.

The effects of phosphatidylserine (PS) were studied in rats treated with reserpine (1 mg/kg) immediately after training in the passive avoidance task. In experiment I, phosphatidylserine (25 mg/kg) was administered 30 min before or immediately after training. Acute pre- or post-treatment with phosphatidylserine was effective in reversing the amnestic effect of reserpine in test trials performed 24 h and 1 week after training. Experiment II was performed to determine if the long-term pretreatment with phosphatidylserine (25 mg/kg) for 7 days is able to protect the rats against the amnestic effects of reserpine in this task. The data show that phosphatidylserine reverses the impairment induced by reserpine in trials performed 24 h and 1 week after training. These results indicate that the memory deficits associated with catecholamine depletion caused by reserpine can be attenuated by acute pre- or post-training or by long-term pretreatment with this phospholipid.

The effect of caffeine in animal models of learning and memory.

In the present investigation we studied the effect of caffeine on memory task inhibitory avoidance and habituation to a new environment. Caffeine impaired retention scores in mice submitted to inhibitory avoidance and habituation when administered 30 min before training at the doses of 10-30 mg/kg. These effects cannot be explained by state-dependency since the administration of caffeine 30 min before the test session did not reverse the effect of pre-training caffeine administration, but can more probably be explained by an impairment in the acquisition or by interference with attentional processes. On the other hand, caffeine improved the inhibitory avoidance (but not habituation) retention scores when administered immediately after the training or 30 min before the test session at the doses of 1-30 mg/kg or 3-10 mg/kg, respectively. These results suggest that caffeine differentially affects the different stages of memory processing and that this effect depends on particularities of the memory task under study.

Long-term follow-up of non-HIV Kaposi's sarcoma treated with low-dose recombinant interferon alfa-2b.

BACKGROUND AND DESIGN: We reviewed the follow-up of 16 patients with Kaposi's sarcoma not related to human immunodeficiency virus (13 with classic Kaposi's sarcoma and three with endemic Kaposi's sarcoma; median age, 58 years) treated by low-dose recombinant interferon alfa-2b (5 million U three times weekly for at least 6 months). RESULTS: One patient had a complete response, nine had a major response, three had stable disease, and one had a minor response. Visceral disease stabilized and symptoms improved in three patients. Limited relapse was noted in four patients after withdrawal of interferon. CONCLUSION: Our results confirm the efficacy and safety of low-dose recombinant interferon alfa-2b in the long-term treatment of both cutaneous and visceral lesions of Kaposi's sarcoma not related to human immunodeficiency virus.

Caffeine reverses the memory disruption induced by intra-nigral MPTP-injection in rats.

The present study was carried out to test the possible effects of caffeine in improving the memory deficits observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP)-lesioned rats, an animal model of early stage Parkinson's disease. Caffeine at the doses of 0.1-0.3 mg/kg (intraperitoneal) reversed the impairing effect of the administration of MPTP (1 micromol/side) into the substantia nigra, compact part, of rats on the avoidance scores in the training and test sessions of a two-way active avoidance task. This effect was not due to a motor or sensory alteration because the caffeine-induced learning and memory improvement was independent of the locomotor stimulant effect of the drug and there were no differences in the reaction time of the animals to a footshock (unconditioned stimulus) or a sound cue (conditioned stimulus) after caffeine treatment. These results suggest that the reported dopamine/adenosine-receptor interaction can be used to restore defective learning and memory processes in Parkinson's disease and indicate that caffeine and other adenosine receptor antagonists are drugs with the potential for treatment of the cognitive disabilities of Parkinson's disease.

Effect of various training procedures on performance in an elevated plus-maze: possible relation with brain regional levels of benzodiazepine-like molecules.

Rats submitted to one, two, or seven sessions of exploration to a new environment (habituation) or exposed to an inhibitory avoidance training showed different degrees of anxiety, evaluated by the elevated plus-maze test. Also, the brain regional levels of benzodiazepine (BDZ)-like molecules in rats submitted to one, two, or seven sessions of habituation were differentially decreased with respect to nontrained rats. The percentage of time spent in the open arms of the elevated plus-maze for each group correlates with the data of decrease in the BDZ-like immunoreactivity in amygdala (r = 0.77, p < 0.0005), hippocampus (r = 0.68, p < 0.0005), and septum (r = 0.57, p < 0.005). These results suggest that the limbic system responds to anxiogenic experiences by changing the BDZ-like molecule levels in relation to the degree of anxiety and/or stress that accompany these experiences.

Pharmacological evaluation of ricinine, a central nervous system stimulant isolated from Ricinus communis.

The extract of the pericarp of castor bean (Ricinus communis) showed some typical central nervous system stimulant effects when administered to mice. The animals became exophthalmic, presented tremors and clonic seizures and died a few minutes after receiving larger doses of the extract. At lower doses the extract improved memory consolidation and showed some neuroleptic-like properties, such as a decrease in exploratory behavior and catalepsy. The memory-improving effect and the seizure-eliciting properties of the extract were also observed with the administration of ricinine, a neutral alkaloid isolated from the extract. However, the neuroleptic-like properties of the extract were not observed with ricinine. As the therapeutic index of ricinine is of the order of 200, the compound may be considered as a promising cognition-enhancing drug that may be used for the treatment of human amnesias.

Ricinine-elicited seizures. A novel chemical model of convulsive seizures.

The present investigation introduces ricinine-elicited seizures as a novel chemical model of convulsive seizure. Ricinine, a neutral alkaloid obtained from the plant Ricinus communis, induces seizures when administered to mice at doses higher than 20 mg/kg. Animals presenting seizures showed a marked preconvulsive phase followed by short duration hind limb myoclonus, respiratory spasms, and death. The lethal nature of ricinine seizures is also pointed out as a good model to study the events causing death in clonic seizures, particularly those related to respiratory spasms, which are also observed in some types of human epilepsy. The behavioral signs of ricinine-elicited seizures are accompanied by electrographic alterations more evident during the preconvulsive phase in the cerebral cortex and more intense during the ictal phase both in the cortex and in the hippocampus. The ricinine-elicited seizures may be inhibited by diazepam but not by phenobarbital, phenytoin, or ethosuximide. Micromolar concentrations of ricinine cause a small decrease in the binding of [3H]-flunitrazepam to cerebral cortex membranes, but do not alter the binding of other radioligands to AMPA, 5-HT(1A), muscarinic, and alpha(1)-adrenergic receptors. Although ricinine presents a cyanide radical, only higher doses of ricinine (4 mM) caused a small impairment of mitochondrial respiration. These results suggest that the mechanism of action of ricinine probably involves the benzodiazepine site in the GABA(A) receptor. This may represent a new mechanism of drug-elicited seizures that may contribute to a better understanding of epilepsy and to new therapeutic approaches to this disease.

Memory modulation by brain benzodiazepines.

1. Recent evidence indicates that post-training memory processes are down-regulated by benzodiazepine/GABA-A systems in the amygdala, septum and hippocampus. Habituation and avoidance learning are accompanied by a decrease of benzodiazepine-like immunoreactivity in the three structures, explainable by a release of benzodiazepines. Immediate post-training microinjection of the benzodiazepine antagonist flumazenil into the hippocampus enhances retention of habituation. The post-training administration of flumazenil into any of the three structures enhances retention of avoidance learning. 2. The mode of operation of these systems was studied in detail in the amygdala using avoidance paradigms. The release of endogenous benzodiazepines during and particularly after training enhances sensitivity of local GABA-A receptors to muscimol, activation of the GABA-A receptors opens chloride channels that can be selectively blocked by picrotoxin and by Ro5-4864. Training enhances, and flumazenil reduces, sensitivity of the amygdala to the amnestic effect of locally injected muscimol by a factor of 100. Post-training intra-amygdala administration of picrotoxin or Ro5-4864 enhances retention. 3. These findings suggest that the endogenous benzodiazepine/GABA-A mechanisms that down-regulate memory in the amygdala, septum and hippocampus are activated in response to the anxiety and/or stress associated with each task. Memory lability which occurs in the post-training period and characterizes consolidation would thus be a consequence of the brain's response to anxiety or stress.