A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

RATIONALE: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. OBJECTIVE: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. METHODS: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. RESULTS: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). CONCLUSIONS: These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.     

The Effect of Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome in a Rat Model of Subarachnoid Hemorrhage

Blood glutamate scavengers have been shown to effectively reduce blood glutamate concentrations and improve neurological outcome after traumatic brain injury and stroke in rats. This study investigates the efficacy of blood glutamate scavengers oxaloacetate and pyruvate in the treatment of subarachnoid hemorrhage (SAH) in rats. Isotonic saline, 250 mg/kg oxaloacetate, or 125 mg/kg pyruvate was injected intravenously in 60 rats, 60 minutes after induction of SAH at a rate of 0.1 ml/100 g/min for 30 minutes. There were 20 additional rats that were used as a sham-operated group. Blood samples were collected at baseline and 90 minutes after SAH. Neurological performance was assessed at 24 h after SAH. In half of the rats, glutamate concentrations in the cerebrospinal fluid were measured 24 h after SAH. For the remaining half, the blood brain barrier permeability in the frontal and parieto-occipital lobes was measured 48 h after SAH. Blood glutamate levels were reduced in rats treated with oxaloacetate or pyruvate at 90 minutes after SAH (p < 0.001). Cerebrospinal fluid glutamate was reduced in rats treated with pyruvate (p < 0.05). Neurological performance was significantly improved in rats treated with oxaloacetate (p < 0.05) or pyruvate (p < 0.01). The breakdown of the blood brain barrier was reduced in the frontal lobe in rats treated with pyruvate (p < 0.05) and in the parieto-occipital lobes in rats treated with either pyruvate (p < 0.01) or oxaloacetate (p < 0.01). This study demonstrates the effectiveness of blood glutamate scavengers oxaloacetate and pyruvate as a therapeutic neuroprotective strategy in a rat model of SAH.     

Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats

Clinical studies have suggested that estrogens may affect the symptoms of schizophrenia. The novel object recognition task (NORT) in female rats treated with sub-chronic phencyclidine (PCP) was used as an animal model of the cognitive deficits in schizophrenia. The current studies investigated whether chronic estradiol (E) could alleviate sub-chronic PCP-induced cognitive deficits in the NORT. Adult Sprague-Dawley rats were ovariectomized (ovx) and treated with either sub-chronic PCP (2 mg/kg bidaily i.p. for seven days), or with 0.9% saline and their object recognition memory was tested with the NORT using an acquisition trial, 1 min inter-trial interval, and retention trial. Sub-chronic PCP administration did not reliably affect behavior in the acquisition trial but significantly impaired object recognition in the retention trial for 1-2 and 27-29 weeks. Ovx females spent significantly (p<0.05) more time exploring the novel compared to the familiar object, whereas PCP-treated ovx females did not. This effect of PCP was attenuated by long-lasting E capsules implanted prior to PCP treatment. PCP-treated females implanted with E again spent significantly more time exploring the novel compared to the familiar object (p<0.01). When ovx rats were treated with sub-chronic PCP and a long-lasting E capsule was implanted either before or after PCP treatment, estradiol alleviated the PCP-induced deficits when administered in either regimen (p=0.01 and p=0.047 respectively). These data suggest that further exploration of estradiol as a possible therapeutic compound to treat the cognitive deficits of schizophrenia is warranted.     

Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population

Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D′ = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls.     

Endoscopy-guided removal of spontaneous intracerebral hemorrhage: comparison with computer tomography-guided stereotactic evacuation

Background and purpose Spontaneous intracerebral hemorrhage (ICH) continues to be a major medical and socioeconomic problem. While the surgical procedure failed to show benefits over functional outcome, a less invasive and quicker surgical decompression might improve the outcome. The authors introduced endoscopy-guided evacuation in managing ICH and reports the benefits over the conventional method. Materials and methods Twenty-seven cases underwent endoscopic evacuation of ICH (Group E). The clinical features and outcomes were compared to the retrospective data of 20 cases who underwent computer tomography (CT)-guided stereotactic removal of ICH (Group C). Confidence level less than 0.05 was considered statistically significant. Results While the clinical features of the two groups were not significantly different except for the ICH volume, outcomes were better in all aspects in Group E. The patients in Group E required shorter operative time (72 min vs 102 min, p < 0.01) with better hematoma evacuation (95.5% vs 75%, p < 0.01), shorter stay in the intensive care unit (ICU; 4.2 days vs 6.9 days, p < 0.01) and less frequent CT scanning (6.4 times vs 8.6 times, p < 0.01) compared to the patients in Group C. Neurological outcome improved significantly in Group E 1 week after surgery (p < 0.01), but not in Group C. Glasgow outcome scale at 6 months were better in Group E than in Group C (p < 0.05). Nine patients (33%) showed good recovery at 6 months postoperatively after endoscopic evacuation of ICH. Conclusion Endoscopic hematoma evacuation provided the quick, adequate decompression of ICH. The outcomes were better than the CT-guided hematoma removal. Further study is necessary to evaluate the real benefit of this surgical procedure over the functional outcome of ICH. Presented at the Third World Conference of the International Study Group on Neuroendoscopy (ISGNE), Marburg, Germany, 15–18 June 2005.     

Cocaine,but not amphetamine,short term treatment elevates the density of rat brain vesicular monoamine transporter 2

Summary We compared the effect of 5 days D-amphetamine (5 mg/kg/day i.p.) and cocaine (15 mg/kg/day i.p.) administration on the vesicular monoamine transporter 2 (VMAT2) density in rat brain. VMAT2 expression was assessed by [³H]dihydrotetrabenazine high affinity binding. Cocaine administration led to significant increases in VMAT2 density in both prefrontal cortex (+40%, p < 0.01) and striatum (+23%, p < 0.05), while amphetamine did not affect VMAT2 expression. The upregulation of VMAT2 may serve as compensatory mechanism aimed to enhance the vesicular monoamine storage capacity.     

Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat

The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195+/-12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p<0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p<0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia.     

Cerebellar Brain-Derived Neurotrophic Factor, Nerve Growth Factor, and Neurotrophin-3 Expression in Male and Female Rats Is Differentially Affected by Hypergravity Exposure During Discrete Developmental Periods

We previously reported that the effects of perinatal exposure to hypergravity on cerebellum and motor functions in rat neonates are strongly dependent on the specific developmental period of exposure. In the present study, we explored the hypothesis that neurodevelopmental changes are associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. We compared the effects of hypergravity exposure during four developmental periods: period I extended from gestational day (G) 8 through G15; period II from G15 to birth, period III from birth to postnatal day (P) 6; and period IV extended from G8–P12. For comparison we used stationary control (SC) neonates not exposed to hypergravity. Neurotrophins, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT-3) levels were measured in cerebellar homogenates prepared from postnatal day 12 male and female rat neonates using specific ELISAs. Hypergravity exposure affected individual neurotrophins differently and the effect was further determined by the period of hypergravity exposure. ANOVA showed: (1) a significant effect of the period of exposure to hypergravity on cerebellar BDNF (p = 0.009), with maximal decrease of 28.7% in males and 32.1% in females following exposure during period III; (2) a significant effect on NGF (p < 0.0001), with maximal decrease of 35.6% in male and 48.8% in female neonates following exposure during period III; (3) no statistically significant effect on NT-3 expression with a trend towards decreased expression in female rats following exposure during period IV. Although the molecular mechanisms underlying the differential neurotrophins’ response to hypergravity are not clear, an altered pattern of their expression is likely to contribute to neurodevelopmental changes and impaired sensorimotor behavior in exposed neonates.     

α-MSH Rescues Neurons from Excitotoxic Cell Death

This study investigates the effects of alpha-melanocyte-stimulating hormone (α-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with α-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 ±  25,554 vs. 145,254 ± 27,871). The number of viable neurons upon administration of α-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 ± 33,158, KA+α-MSH vs. 79,587 ± 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1β levels was delayed by the treatment with α-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of α-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of α-MSH has rescuing effects on neurons subjected to excitotoxic insults.     

New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS)

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype–phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype–phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher’s exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 ± 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869–878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 ± 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.     

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Alterations of regional brain activity in the prefrontal cortex and in limbic areas have been reported in humans with anxiety disorders. This animal study reports the results of brain perfusion imaging with single photon emission computed tomography (SPECT) in dogs with anxiety disorders. Based on the human literature, we hypothesized altered prefrontal and higher temporal brain perfusion. SPECT acquisitions were performed using the ^99mTc-labelled tracer ethyl cysteinate dimer (ECD). Eighteen dogs with pathological anxiety were compared with 18 normally behaving reference dogs. We found, in the group of dogs with anxiety disorders, lower perfusion in the left frontal cortex (p = 0.003), in the subcortical region (p = 0.007) and increased perfusion in the right (p = 0.05) temporal cortex. Taken together, our rCBF findings are suggestive for a dysfunction of the prefrontal cortex and the limbic system in canine anxiety disorders.     

Circulating B7-H3(CD276) Elevations in Cerebrospinal Fluid and Plasma of Children with Bacterial Meningitis

The objective of this study was to analyze the clinical significance of cerebrospinal fluid (CSF) and plasma concentrations of B7-H3, tumor necrosis factor-alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-17 (IL-17) in bacterial and aseptic meningitis in children. The participants were six children with bacterial meningitis, 16 with aseptic meningitis, and 12 control subjects. All participants were between 2 months and 12 years of age on admission. Cytokines determination was performed by enzyme-linked immunosorbent assay technique. CSF and plasma-circulating B7-H3 were significantly higher in the bacterial meningitis group as compared with the aseptic group (p = 0.001) and the control group (p = 0.000 and p = 0.001 respectively). However, CSF and plasma-circulating B7-H3 in aseptic meningitis were not significantly higher than control group (p = 0.071 and p = 0.72 respectively).CSF and plasma-circulating TNF-α were significantly higher in the bacterial meningitis group as compared with the aseptic group (p = 0.004 and p < 0.0001 respectively) and control group (p = 0.004 and p < 0.0001 respectively). Similarly, we did not observe significant elevated TNF-α levels in CSF and plasma in aseptic group compared with control group (p = 0.03 and p = 0.12 respectively). IFN-γ levels in CSF and plasma were undetectable in control group, and we did not find statistical significances in both of CSF and plasma between the elevated IFN-γ level in bacterial meningitis group and aseptic meningitis group(p = 0.055 and p = 0.095 respectively) CSF and plasma levels of IL-17 were undetectable in all subjects. There were correlations between B7-H3 and TNF-α, IFN-γ (r = 0.875, p = 0.000; r = −0.693, p = 0.000, respectively) in CSF in meningitis subjects. In plasma, levels of B7-H3 in bacterial meningitis on admission correlated positively with TNF-α (r = 0.968, p = 0.002), and white blood cell counts (r = 0.973, p = 0.001). Detectable CSF levels of B7-H3, TNF-α, and IFN-γ on admission were not associated significantly with any of CSF characteristics. Additionally, CSF and plasma levels of B7-H3 decreased remarkably after treatment. Altogether, our data indicated that circulating B7-H3 and TNF-α levels in the CSF and plasma were useful markers for distinguishing bacterial from aseptic meningitis, and Circulating B7-H3 was demonstrated to be useful in evaluating the intensity of the infectious inflammatory process in the central nervous system in children. An erratum to this article can be found at     

Alteration of serum semicarbazide-sensitive amine oxidase activity in chronic renal failure

Summary Despite recent intensive investigations, physiological and pathological role of semicarbazide-sensitive amine oxidase (SSAO) is far from clear. In this study, serum SSAO activity was determined, radiochemically, in various groups of uremic patients: haemodialysed (HD), peritoneally dialysed (PD) and those receiving conservative treatment but still not dialysed (ND), as well as in controls. Reduced enzyme activity was found in HD uremic patients before and after dialysis treatment, compared to controls (5260 ± 862 and 6011 ± 958 pmol/h/ml vs. 8601 ± 283 pmol/h/ml, p < 0.01 and p < 0.05, respectively). The activity was slightly lower in PD, and normal in ND patients. In HD patients SSAO activity was also determined by an assay based on the formation of hydrogen peroxide, and was found to be elevated compared to controls (2384 ± 323 pmol/h/ml vs. 1437 ± 72 pmol/h/ml, p < 0.05). The elevated serum SSAO activity measured through the detection of the enzyme-generated hydrogen peroxide in HD patients might indicate its contribution to the accelerated atherosclerotic disease observed in uremia.     

Reduced expression of synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia

Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)—a N‐methyl‐D‐aspartate (NMDA) receptor antagonist—induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well‐known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini‐pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper‐locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre‐pulse inhibition (p < 0.0001) in comparison to saline‐treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer‐term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.     

Analysis of Olfactory Ensheathing Glia Transplantation-Induced Repair of Spinal Cord Injury by Electrophysiological,Behavioral, and Histochemical Methods in Rats

This study examined the efficacy of transplanting olfactory ensheathing glia (OEG) in repairing spinal cord injury (SCI) using behavioral tests, retrograde labeling, as well as somatosensory and motor evoked potentials in rats. One week after surgery, motor function in OEG-treated rats was significantly superior to untreated controls (P < 0.05). Also, we found that up to 8 weeks following surgery to induce SCI, somatosensory and motor evoked potentials were found in the OEG-treated groups, but not in the transplantation and damage control groups. Retrograde labeling from the area distal to the SCI produced a higher number of labeled neurons in the ventrolateral division of red nucleus and motor cortex of OEG-treated rats compared to controls, which showed no retrograde labeling (P < 0.05). We believe that this study has important implications for characterizing the mechanisms of OEG transplantation as a treatment for SCI.     

Sex differences in brain MRI abnormalities and neurodevelopmental outcomes in a rat model of neonatal hypoxia-ischemia

Purpose/aim of the study: Hypoxic-ischemic brain injury (HIBI) is associated with high mortality and neurodevelopmental deficits. We explored gender influence in a HIBI rat model. Materials and methods: Sprague–Dawley rats underwent HIBI on postnatal day (P) 7. Nervous reflexes, footprints, Morris water maze performances and magnetic resonance imaging (MRI) were analyzed. Results: Mortality rate was higher in HIBI males (20%) than in females (12.5%). Growth rate was slower in the HIBI group (p < 0.05), but was similar between HIBI males and females. HIBI rats showed impaired performances in the cliff aversion reflex, negative geotaxis reflex and gait tests at P14 (p < 0.05), but not at P9 or P11. There were no significant differences for the cliff aversion reflex and gait tests between genders. Negative geotaxis reflex impairment at P14 was more severe in HIBI males (p < 0.05). Step length and toe distance contralateral (but not ipsilateral) to the cerebral damage were shorter in HIBI rats, and were shorter in HIBI males than females (p < 0.05). Morris water maze latency time and swimming distance were longer in the HI group than in controls, and prolonged in HIBI males compared with females (p < 0.05). In the HIBI group, MRI showed more severe injury at P10 and P67 in males than in females (p < 0.05). Conclusions: Male rats are more vulnerable to the detrimental consequences of HIBI, with more severe nervous reflex deficits, brain injury, memory impairment and hemiplegic paralysis than female rats. Serial neurobehavioral follow-up is still executed on the HIBI infants who is absent of detectable abnormalities in early children.     

Effects of brain-derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease

Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of developing motor neurons in vitro and to rescue motor neurons from axotomy-induced cell death in vivo. In this study, we examined the effects of exogenous BDNF on the progression of wobbler mouse motor neuron disease (MND). After clinical diagnosis at age 3 to 4 weeks, 20 affected mice received subcutaneous injections of recombinant human BDNF (5 mg/kg, n = 10) or vehicle (n = 10), three times a week for 4 weeks. In a separate experiment done to conduct a histometric analysis of the C-5 and C-6 ventral roots and to determine the number of myelinated nerve fibers, 7 wobbler mice received identical BDNF treatment. In the 10 BDNF-treated wobbler mice, grip strength declined at a slower rate (p < 0.03) and was twice as great as that of vehicle-treated animals at the end of treatment (p < 0.01). In vivo biceps (p < 0.01-) and in vitro muscle twitch tensions (p < 0.02) were also greater than those of vehicle-treated mice. The biceps muscle weight was 20% greater (p < 0.05) and the mean muscle fiber diameter was significantly larger in BDNF-treated mice (p < 0.001) because the number of small (denervated) muscle fibers was markedly reduced. The number of myelinated motor axons at the cervical ventral roots studied in the additional 7 affected mice was 25% greater with BDNF treatment (p < 0.0001). This study establishes that exogenous BDNF administration can retard motor dysfunction in a natural MND and diminish denervation muscle atrophy and motor axon loss.     

A fMRI Study of Verbal Working Memory, Cardiac Output, and Ejection Fraction in Elderly Patients with Cardiovascular Disease

Cardiovascular disease (CVD) is associated with cognitive deficits even in the absence of stroke. We examined the relationship between cardiac performance, as measured by cardiac output (CO) and ejection fraction (EF), and brain activity during a verbal working memory (VWM) task in elderly CVD patients who tend to be at increased risk for vascular cognitive impairments. Seventeen patients were recruited from a cohort participating in an ongoing prospective study examining the effects of CVD on cognitive function in the elderly. Participants were diagnosed with CVD (age 68 ± 8) and completed a 2-back VWM task in a 1.5T fMRI paradigm. CO and EF were calculated from echocardiogram measures. Task-related activation was averaged in a priori regions of interest. The relationship between CO, EF, and 2-back-related activity was modeled using partial correlations (two-tailed p < .05) controlling for age and 2-back accuracy. All participants were globally cognitively intact as indicated by Mini-Mental Status Exam and Dementia Rating Scale scores. Mean accuracy on the 2-back was 78 ± 9% while reaction time averaged 1,027 ± 192 ms. Mean CO and EF values showed a large range (CO: 3.55 to 6.31; EF: 0.36 to 0.76) but average values were within the normal range. After controlling for age and 2-back accuracy, lower EF was related to decrease in left insula activity (r = 0.61, p = 0.03). There were trends for EF to be related to accuracy (r = 0.47, p = 0.09) and reaction time (r = −0.48, p = 0.09). CO was also related to insula activity (r = 0.60, p = 0.04) and activity in the supplementary motor area activity (r = 0.66, p = 0.01). Cardiac performance was related to decreased efficiency in task related brain areas and tended to be related to performance on a VWM task in elderly patients with CVD. Results have implications for a line of investigation indicating that cardiac and systemic vascular indices could be used as proxy measures to examine mechanisms of cerebrovascular dysfunction in the elderly.     

Dopamine D<Subscript>1</Subscript> Receptor Gene Expression Studies in Unilateral 6-Hydroxydopamine-Lesioned Parkinson’s Rat: Effect of 5-HT,GABA, and Bone Marrow Cell Supplementation

Parkinson’s disease is the second most common neurodegenerative disorder and remains incurable. Many potential compensatory mechanisms have now been proposed; these are both dopaminergic, focused on enhancing effects or exposure to existing dopamine, and non-dopaminergic, being focused on reducing activity of the indirect striatal output pathway. In the present study, the effects of serotonin, gamma-aminobutyric acid, and bone marrow cell supplementation intranigrally to the substantia nigra on unilateral 6-hydroxydopamine-infused rats were analyzed individually. Dopaminergic binding parameters were done by Scatchard analysis of dopamine D₁ receptor-binding assay using [³H]SCH 23390. In the corpus striatum, 6-hydroxydopamine-infused rats showed a significant decrease in B _max (P < 0.001), and in cerebral cortex, they showed a significant increase in B _max (P < 0.001) compared to control. Real-time polymerase chain reaction amplification of dopamine D₁ was downregulated (P < 0.001) in the corpus striatum of 6-hydroxydopamine-infused rats compared to control, whereas in the cerebral cortex, it showed a significant upregulation (P < 0.001). Behavioral studies were carried out to confirm the biochemical and molecular studies. Serotonin and gamma-aminobutyric acid supplementation reversed these changes to control. The bone marrow cell-treated group of our studies does not show much significant change as compared to the serotonin and gamma-aminobutyric acid-supplemented groups. The alterations in dopamine D₁ receptor-binding parameters and gene expression during Parkinson’s model were reversed by serotonin and gamma-aminobutyric acid supplementation in our experiments, which has clinical significance in the management of the disease.