Characterization of juvenile and young adult mice following induction of hydrocephalus with kaolin

Hydrocephalus is a common neurological problem in humans, usually caused by an impairment of cerebrospinal fluid (CSF) flow or absorption. A reliable induced model of chronic hydrocephalus in mice would be useful to test hypotheses using genetic mutants. Our goal was to characterize behavioral and histological changes in juvenile and young adult mice with kaolin (aluminum silicate)-induced hydrocephalus. Seven-day old and 7–8 week old mice received injection of kaolin into the cisterna magna. Behavior was assessed repeatedly. Seven or 14 days following kaolin, magnetic resonance (MR) imaging was used to assess ventricle size. In hydrocephalic mice, body weight was significantly lower than in age-matched saline-injected sham controls and the gait and posture score were impaired. Juvenile mice developed severe ventriculomegaly and had reduced corpus callosum thickness with gross white matter destruction by 14 days. Reactive astroglial change in white matter and cortex and reduced cellular proliferation in the subependymal zone were also apparent. Young adult mice developed only moderate ventricular enlargement without overt white matter destruction, although there was corpus callosum atrophy and mild astroglial reaction in white matter. Glial fibrillary acidic protein content was significantly higher in juvenile and young adult hydrocephalic mice at 7 and 14 days, but myelin basic protein content was not significantly altered. In conclusion, hydrocephalus induced by percutaneous injection of kaolin in juvenile and young adult mice is feasible. The associated periventricular alterations are essentially the same as those reported in rats of comparable ages.     

Learning deficits in congenitally hydrocephalic rats and prevention by early shunt treatment

Shunt surgery is the usual treatment for infantile hydrocephalus; however, the extent to which it avoids subsequent neurological deficits is uncertain. The effect of early-onset hydrocephalus was tested in H-Tx rats using the Morris water maze. Spatial learning was assessed at 21 days after birth in control (n=18), hydrocephalic (n=18) and hydrocephalic rats shunt-treated at 4–5 (n=7) or at 10–12 days of life (n=13). The time taken to find a hidden platform was measured in five trials on 2 consecutive days and the data analyzed by one-and two-way ANOVA and t-tests. The latencies of the control rats decreased significantly between the first and second trial on the 1 st day, and learning was retained until the 2nd day. The hydrocephalic group had longer latencies than controls on both days, with no significant decrease between any trials. Performance was not significantly different between the two shunt groups. Overall, the shunted rats had latencies which were not significantly different from controls but were significantly lower than hydrocephalics. Despite this, the shunted rats did not perform as well as the controls. It is concluded that, although shunt treatment improved learning, some effects of early-onset hydrocephalus may not be reversible and/or a longer recovery time is required.     

Post-ischemic leakiness of the blood–brain barrier: A quantitative and systematic assessment by Patlak plots

The Patlak plot analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows estimation of blood–brain barrier (BBB) leakage following temporary focal cerebral ischemia. Thus far, a systematic and quantitative in vivo evaluation of post-ischemic BBB leakage is lacking. Here, using DCE-MRI and the Patlak plot method, we quantitatively assessed BBB leakage in rats at the following time-points after reperfusion: 25 min, 2, 4, 6, 12, 18, 24, 36, 48, and 72 h, and 1, 2, 3, 4, and 5 weeks. Sham-operated animals served as controls. Data collected for each time-point were: the blood-to-brain transfer rate constant (K_i) of the contrast agent gadolinium, distribution volume (V_p), ischemic lesion volume, and apparent diffusion coefficient (ADC) values. Compared to controls, K_i, measured at all time-points, except for 5 weeks, appeared significantly different (p < 0.001). At several time-points (25 min, 48 and 72 h, 4 and 5 weeks), V_p was similar compared to that of controls, but for the remaining groups the difference was significant (p < 0.001). Analyzing the relationship of K_i values to time-points, we observed a trend towards a decrease over time (r = − 0.61, p = 0.014). Both ADC values (r = − 0.58, p = 0.02) and ischemic lesion volumes (r = 0.75, p = 0.0015) correlated with K_i values. These results suggest that after ischemia–reperfusion in rats, BBB leakage is continuous during a 4-week period. Its magnitude diminishes over time and correlates with severity and extent of ischemic injury.     

LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia

Platelet-activating factor (PAF) is a bioactive phospholipid that accumulates during ischemia-reperfusion and is involved in the activation of platelets, neutrophils, and pro-inflammatory signaling. PAF has been suggested to enhance brain ischemia-reperfusion damage. LAU-0901, a novel PAF receptor antagonist, was examined in models of focal cerebral ischemia in rats and mice. Sprague–Dawley rats were anesthetized and received 2-hour middle cerebral artery occlusion (MCAo) by intraluminal suture. LAU-0901 (30, 60, 90 mg/kg; n = 9–11) or vehicle (n = 11) was administered i.p. at 2 h after onset of MCAo. The neurological status was evaluated at 60 min, and on days 1, 2, 3 and 7 after MCAo. In the dose–response study in mice, C57BL/6 mice were anesthetized and received 1 h MCAo by intraluminal suture. LAU-0901 (15, 30, 60 mg/kg; n = 7–9) or vehicle (n = 8) was given i.p. at 1 h after onset of MCAo. Local cerebral blood flow (LCBF) was measured at 1, 2, 4, and 6 h after MCAo in mice. LAU-0901 treated rats showed improved neurological score throughout the 7-day survival period. LAU-0901 treatment (30, 60 and 90 mg/kg) reduced total corrected infarct volume compared to vehicle rats by 76, 88 and 90%, respectively. Mice treated with LAU-0901 (30 and 60 mg/kg) reduced total infarction by 29% and 66%, respectively. LCBF was improved by treatment with LAU-0901 (30 mg/kg) by 77% of baseline at 6 h. In conclusion, we demonstrate for the first time that LAU-0901 improves behavioral scores, LCBF and reduces infarct volume after focal cerebral ischemia in rats and mice. Thus, this PAF receptor antagonist exhibits potent and sustained neuroprotection that may be of value for the design of stroke therapies.     

A straight alley version of the BBB locomotor scale

We describe here an alternative procedure for assessing hindlimb locomotor function after spinal cord injury that uses the BBB scale, but tests animals in a reward-baited straight alley rather than an open field. Rats were trained to ambulate in a straight alley and habituated to the open field typically used for BBB open field testing. Three groups of rats were tested. Sprague–Dawley rats received either 200 kD (n = 19) or 300 kD contusions (n = 9) at T9 with the Infinite Horizon device. Fisher rats (n = 8) received moderate contusions (12.5 mm) at T8 with the NYU impactor. BBB scores were assessed at different post-injury intervals in the open field and the straight alley, and scores were compared by correlation analyses. BBB scores in the open field vs. the straight alley were highly correlated (r = 0.90), validating the use of the straight alley for locomotor assessment. Rats exhibited a larger number of bouts of continuous steps in the straight alley vs. the open field (termed passes), providing more opportunities to score hindlimb use and coordination over the 4 min testing interval. Comparisons of scores across days revealed higher day-to-day correlations in the straight alley vs. the open field (r² values of 0.90 and 0.74 for the straight alley and open field respectively), revealing that the straight alley yielded more reliable scores.     

Pharmacokinetics of olanzapine in Chinese male schizophrenic patients with various smoking behaviors

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose–plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers (n = 9), light-smokers (1–4 cigarettes per day; n = 9), and heavy-smokers (≥ 5 cigarettes per day; n = 9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers (n = 9; 0.79; p = 0.01) or combined with light-smokers (n = 18; 0.62; p < 0.01) between peak plasma olanzapine concentrations (C_max) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC_0→120 by 45.1% in light-smokers. The mean C_max and the mean area under the plasma concentration–time curve from time zero to 120 h (AUC_0→120) of the heavy-smoking patients was 9.3 ± 4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4 ± 167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50–100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.     

Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats

Hemorrhagic transformation (HT) and brain edema are life-threatening complications of recombinant tissue plasminogen activator (rt-PA)-induced reperfusion after ischemic stroke. The risk of HT limits the therapeutic window for reperfusion to 3 h after stroke onset. Pre-treatment with matrix metalloproteinase (MMP) inhibitors reduces HT and cerebral edema in experimental stroke. However, whether a delayed therapeutic intervention would be beneficial is unknown. In this study, 215 male Sprague–Dawley rats were subjected to embolic stroke and 75 rats were included in the final analysis. The animals were treated with the MMP inhibitor p-aminobenzoyl-gly-pro-d-leu-d-ala-hydroxamate before or after 3 or 6 h of ischemia. Animals were monitored for reperfusion and received rt-PA 6 h after ischemia onset. The results at 24 h showed that MMP inhibition 3 h after ischemia significantly decreased the degree of brain edema (17% of hemispheric enlargement in the treated group versus 24% in controls, P = 0.018), reduced the risk (OR = 0.163; 95% CI: 0.029 to 0.953) and gravity (0.09 versus 0.19 mg of parenchymal hemoglobin, P = 0.02) of intracerebral hemorrhage, and improved neurological outcome (20% of the treated animals had a slight deficit; all of the controls had a bad outcome, P < 0.05). Delaying MMP inhibition to 6 h after ischemia restricted the beneficial role of the treatment to a reduction in the risk of parenchymal hemorrhage (OR = 0.242; 95% CI: 0.060 to 0.989). Our results confirm the involvement of MMPs in HT and support the possibility of extending the therapeutic window for thrombolysis in stroke by administering a broad-spectrum MMP inhibitor after the onset of ischemia.     

Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-κB pathway

Simvastatin, a cholesterol-lowering agent, has demonstrated neuroprotective effects against brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of simvastatin on the Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) related signaling pathway and secondary brain injury in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into four groups: (1) Sham group (n = 25); (2) Sham + vehicle group (n = 25); (3) TBI + vehicle group (n = 30); and (4) TBI + simvastatin group (n = 30). Right parietal cortical contusion was made by using a weight-dropping method. In TBI + simvastatin group, simvastatin was administered orally at a dose of 37.5 mg/kg at 1 and 6 h after TBI. Brain samples were extracted at 24 h after trauma. As a result, we found that treatment with simvastatin markedly inhibited the mRNA and protein expressions of TLR4, NF-κB and the downstream inflammatory agents, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1). Administration of simvastatin following TBI significantly ameliorated the secondary brain damage, such as cortical apoptosis, brain edema, blood–brain barrier (BBB) impairment, and motor deficits. In conclusion, post-TBI simvastatin administration may attenuate TLR4/NF-κB-mediated inflammatory response in the injured rat brain, and this may be one mechanism by which simvastatin improves outcome following TBI.     

Ventricular dilation and elevated aqueductal pulsations in a new experimental model of communicating hydrocephalus

In communicating hydrocephalus (CH), explanations for the symptoms and clear-cut effective treatments remain elusive. Pulsatile flow through the cerebral aqueduct is often significantly elevated, but a clear link between abnormal pulsations and ventriculomegaly has yet to be identified. We sought to demonstrate measurement of pulsatile aqueductal flow of CSF in the rat, and to characterize the temporal changes in CSF pulsations in a new model of CH. Hydrocephalus was induced by injection of kaolin into the basal cisterns of adult rats (n  =  18). Ventricular volume and aqueductal pulsations were measured on a 9.4 T MRI over a one month period. Half of the animals developed ventricular dilation, with increased ventricular volume and pulsations as early as one day post-induction, and marked chronic elevations compared to intact controls (volume: 130.15 ± 83.21 μl vs. 15.52 ± 2.00 μl; pulsations: 114.51 nl ± 106.29 vs. 0.72 ± 0.13 nl). Similar to the clinical presentation, the relationship between ventricular size and pulsations was quite variable. However, the pulsation time-course revealed two distinct sub-types of hydrocephalic animals: those with markedly elevated pulsations which persisted over time, and those with mildly elevated pulsations which returned to near normal levels after one week. These groups were associated with severe and mild ventriculomegaly respectively. Thus, aqueductal flow can be measured in the rat using high-field MRI and basal cistern-induced CH is associated with an immediate change in CSF pulsatility. At the same time, our results highlight the complex nature of aqueductal pulsation and its relationship to ventricular dilation.     

Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration

Because accumulation of α-synuclein (αS) in the brain is a hallmark of Parkinson disease (PD) and related disorders, we examined its occurrence in human cerebrospinal fluid (CSF). Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several αS-derived peptides by mass spectrometry. The concentration of αS amounted to < 0.001% of the CSF proteome. We then built, validated and optimized a sandwich-type, enzyme-linked immunoadsorbent assay (ELISA) to measure total αS levels in unconcentrated CSF. In a cross-sectional study of 100 living donors, we examined cell-free CSF samples from subjects clinically diagnosed with advanced PD, dementia with Lewy bodies (DLB), Alzheimer disease (AD), and a group of non-neurodegenerative disease controls (NCO). In these four groups the CSF αS concentrations ranged from 0.8 to 16.2 pg/μl. Mean CSF αS values were lower in donors with a primary synucleinopathy (PD, DLB: n = 57) than in the other two groups (AD, NCO: n = 35; p = 0.025). By contrast, living Creutzfeldt–Jakob disease patients showed markedly elevated CSF αS levels (n = 8; mean, 300 pg/μl; p < 0.001). Our results unequivocally confirm the presence of αS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF αS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF αS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.     

A preliminary investigation of the impact of maternal obsessive-compulsive disorder and panic disorder on parenting and children

Although there is evidence for the intergenerational transmission of anxiety disorders, there is little research in relation to specific parental disorders. This study evaluated three groups of mothers with at least one child aged 7–14, defined in terms of maternal obsessive-compulsive disorder (OCD; n = 23), panic disorder (n = 18), and healthy controls (n = 20). Parental perceptions and symptomatology, general and disorder-specific child symptoms and mother–child interactions were investigated using self-report, informant report and independent assessment. Mothers with OCD and panic disorder expressed high levels of concern about the impact of their anxiety disorder on their parenting. Group differences in terms of child anxiety were subtle rather than clinically significant. In interactions, anxious mothers were less warm and promoting of psychological autonomy than healthy controls, and they exhibited elevated expressed emotion. Overall, the results suggested a mix of effects including trans-diagnostic and disorder-specific issues. Implications for future research are discussed.     

Localized tetanus in immunized mice

The capacity of tetanus toxin to enhance motor neuron excitability has suggested its potential use as a therapeutic. Widespread active vaccination against tetanus in all developed countries is considered the major obstacle to clinical use of the toxin. We wished to determine the response to localized intramuscular injection of tetanus toxin in both passively and actively immunized animals as an initial exploration into the possible use of tetanus toxin as a clinical therapeutic. Unvaccinated mice (n = 18) underwent intramuscular injection of tetanus toxin into the gastrocnemius muscle (0.2 ng, 1 ng, 5 ng). All animals in the lowest dose group developed only local tetanus of the injected limb of at least 2 weeks duration, while all animals in the higher dose groups also rapidly developed generalized tetanus and were euthanized. Another group of mice (n = 20) received anti-tetanus immunoglobulin (20–40 IU) at the time of toxin injection. These animals although dramatically resistant to the toxin developed predominantly local tetanus for over one month at doses of 2.5 μg and 5.0 μg. A third group of mice (n = 30) underwent active vaccination with tetanus toxoid to induce protective anti-tetanus immunity and then was challenged with high dose toxin injection (5 ng, 50 ng, 0.5 μg, 1.25 μg, 2.5 μg, or 5 μg). All animals developed local tetanus in the injected limb at a dose of at least 0.5 μg. The severity and duration of local tetanus was generally related to dose, but was more variable in the actively vaccinated group than in the naive or passively immunized animals. Response to the toxin over the first few days was predictive of both the duration and maximal severity of the motor response. Although vaccination dramatically increases resistance to tetanus toxin, by virtue of its extremely high potency, the toxin can produce prolonged localized tetanus even in vaccinated animals with relatively small amounts of protein. These results suggest the possible use of tetanus toxin to enhance local motor activity in a variety of neurologic conditions even in immunized humans. This study in uniformly vaccinated animals also illustrates the potential difficulties in determining an appropriate dose of toxin in a human population with variable degrees of immunity.     

Behavioral and histological assessment of the effect of intermittent feeding in the pilocarpine model of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most resistant type of epilepsy. Currently available drugs for epilepsy are not antiepileptogenic. A novel treatment for epilepsy would be to block or reverse the process of epileptogenesis. We used intermittent feeding (IF) regimen of the dietary restriction (DR) to study its effect on epileptogenesis and neuroprotection in the pilocarpine model of TLE in rats. The effect of IF regimen on the induction of status epilepticus (SE), the duration of latent period, and the frequency, duration, severity and the time of occurrence of Spontaneous Recurrent Seizures (SRS) were investigated. We also studied the effect of IF regimen on hippocampal neurons against the excitotoxic damage of prolonged SE (about 4 h) induced by pilocarpine. The animals (Wistar, male, 200–250 g) were divided into four main groups: AL–AL (ad libitum diet throughout), AL–IF (PfS) [IF post-first seizure], AL–IF (PSE) [IF post-SE] and IF–IF (IF diet throughout), and two AL and IF control groups. SE was induced by pilocarpine (350 mg/kg, i.p.) and with diazepam (6 mg/kg, i.p.) injected after 3 h, the behavioral signs of SE terminated at about 4 h (AL animals, n = 29, 260.43 ± 8.74 min; IF animals, n = 19, 224.32 ± 20.73 min). Behavioral monitoring was carried out by 24 h video recording for 3 weeks after the first SRS. Rat brains were then prepared for histological study with Nissl stain and cell counting was done in CA1, CA2 and CA3 regions of the hippocampus. The results show that the animals on IF diet had significantly less SE induction and significantly longer duration of latent period (the period of epileptogenesis) was seen in IF–IF group compared to the AL–AL group. The severity of SRS was significantly more in AL–IF (PfS) compared to the AL–IF (PSE) group. These results indicate that IF diet can make rats resistant to the induction of SE and can prolong the process of epileptogenesis. The results of the histological study show that the number of pyramidal neurons was statistically less in CA1, CA2 and CA3 of the hippocampus in the experimental groups compared to the control groups. However, IF regimen could not protect the hippocampal neurons against the excitotoxic injury caused by a prolonged SE. We conclude that IF regimen can significantly influence various behavioral characteristics of pilocarpine model of TLE. Further studies can elaborate the exact mechanisms as well as its possible role in the treatment of human TLE.     

Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies

Annonacin, a natural lipophilic inhibitor of mitochondrial complex I has been implicated in the etiology of a sporadic neurodegenerative tauopathy in Guadeloupe. We therefore studied further compounds representing the broad biochemical spectrum of complex I inhibitors to which humans are potentially exposed.We determined their lipophilicity, their effect on complex I activity in submitochondrial particles, and their effect on cellular ATP levels, neuronal cell death and somatodendritic redistribution of phosphorylated tau protein (AD2 antibody against pS396/pS404-tau) in primary cultures of fetal rat striatum.The 24 compounds tested were lipophilic (logP range 0.9–8.5; exception: MPP⁺ logP = − 1.35) and potent complex I inhibitors (IC₅₀ range 0.9 nM–2.6 mM). They all decreased ATP levels (EC₅₀ range 1.9 nM–54.2 μM), induced neuronal cell death (EC₅₀ range 1.1 nM–54.5 μM) and caused the redistribution of AD2⁺ tau from axons to the cell body (EC₅ range 0.6 nM–33.3 μM). The potency of the compounds to inhibit complex I correlated with their potency to induce tau redistribution (r = 0.80, p < 0.001).In conclusion, we propose that the widely distributed lipophilic complex I inhibitors studied here might be implicated in the induction of tauopathies with global prevalence.     

Association of adolescent catatonia with increased mortality and morbidity: Evidence from a prospective follow-up study

This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1–10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age = 19.5 years, range 15–26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N = 20), major depressive episode (N = 5), bipolar disorder type I (N = 4) and brief psychotic episode (N = 2). Mortality (all-cause Standardized Mortality Ratio = 6266; 95% CI = 1181–18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N = 8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up.Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR = 221; 95% CI = 156–303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR = 157; 95% CI = 153–160; Harris and Barraclough, 1998).     

Drug/nutrition interaction in the developing brain: Dipyrone enhances spreading depression in rats

The abuse of pharmaceutical drugs and the inadequate ingestion of nutrients constitute external factors that can alter brain development, both individually and in combination. We used cortical spreading depression (CSD) as a neurophysiological parameter to investigate the combined effects of the antipyretic/analgesic/anti-inflammatory drug dipyrone and malnutrition (M) in the developing rat brain. Suckling malnourished rats (M; n = 69) and well nourished controls (W; n = 76) received dipyrone (300 mg/kg/day) or saline per gavage for 7 consecutive days during the 2nd, 3rd, or 4th postnatal week. At 35–45 days, CSD was recorded at 2 points in the parietal region. In both groups, dipyrone increased CSD propagation velocities compared to respective saline controls (P < 0.05). This effect was intensified when dipyrone application during the 4th postnatal week intensified the increase compared to the 2nd and 3rd weeks. In saline-treated groups, the velocities (mean ± s.d., in mm/min) were 3.70 ± 0.11, 3.77 ± 0.16, and 3.78 ± 0.13 (W) and 4.13 ± 0.10, 4.16 ± 0.10, and 4.14 ± 0.09 (M), for animals treated in the 2nd, 3rd and 4th postnatal weeks. In dipyrone-treated groups, the respective values were 3.99 ± 0.14, 4.03 ± 0.16, and 4.30 ± 0.19 (W) and 4.47 ± 0.17, 4.70 ± 0.31, and 5.01 ± 0.28 (M). Results support the hypothesis that dipyrone has a CSD-facilitating effect, which is more intense at a late brain developmental stage and is facilitated by malnutrition. This may help explain the developmental brain excitability changes that are associated with pharmacological and nutritional factors.     

Forelimb locomotor assessment scale (FLAS): Novel assessment of forelimb dysfunction after cervical spinal cord injury

We describe here a novel forelimb locomotor assessment scale (FLAS) that assesses forelimb use during locomotion in rats injured at the cervical level. A quantitative scale was developed that measures movements of shoulder, elbow, and wrist joints, forepaw position and digit placement, forelimb–hindlimb coordination, compensatory behaviors adopted while walking, and balance. Female Sprague-Dawley rats received graded cervical contusions ranging from 200 to 230 (“mild,” n = 11) and 250–290 kdyn (“moderate,” n = 13) between C5 and C8. Rats were videotaped post-injury as they walked along an alley to determine deficits and recovery of forelimb function. Recovery of shoulder and elbow joint movement occurred rapidly (within 1–7 days post-injury), whereas recovery of wrist joint movement was slower and more variable. Most rats in all groups displayed persistent deficits in forepaw and digit movement, but developed compensatory behaviors to allow functional forward locomotion within 1–2 weeks post-injury. Recovery of forelimb function as measured by the FLAS reached a plateau by 3 weeks post-injury in all groups. Rats with mild contusions displayed greater locomotor recovery than rats with moderate contusions, but exhibited persistent deficits compared to sham controls. Reliability was tested by having seven raters (three internal, four external) from different laboratories, independently and blindly score videos of all rats. The multivariate correlation between all raters, all animals, and all time points ranged from r² = 0.88–0.96 (p < 0.0001), indicating a high inter-rater reliability. Thus, the FLAS is a simple, inexpensive, sensitive, and reliable measure of forelimb function during locomotion following cervical SCI.     

Hyposialorrhea as an early manifestation of Parkinson disease

We sought to determine whether hyposialorrhea is an early manifestation of Parkinson disease (PD). We measured basal and citric acid stimulated secretion of whole saliva in 20 patients with early stage (Hoehn–Yahr I–II) PD who had motor symptoms for less than 1 year and were on no medication and 11 age matched controls. Compared to controls, PD patients had significant reduction of both basal (0.0964 ± 0.08 vs 0.293 ± 0.112 ml/min, p < 0.001) and reflex (0.263 ± 0.213 vs 0.537 ± 0.313 ml/min, p < 0.001) salivary secretion. Our findings confirm that hyposialorrhea is an early autonomic manifestation of PD.     

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in perinatal asphyxia

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) play important roles in the function of the blood–brain-barrier (BBB). We investigated the roles of MMP-9 and TIMP-1 in the pathogenesis of hypoxic–ischemic encephalopathy following perinatal asphyxia. Serum concentrations of MMP-9 and TIMP-1 were determined by ELISA in 12 neonates with perinatal asphyxia and 15 controls on the birth day and the next day. Serum MMP-9 concentrations in asphyxiated neonates with neurological sequelae (n = 5) were significantly higher than concentration in asphyxiated neonates without sequelae (n = 7) and controls on birth day (p = 0.003 and p < 0.001, respectively). The ratios of serum MMP-9/TIMP-1 on birth day in asphyxiated neonates with neurological sequelae were significantly higher than those in asphyxiated neonates without sequelae (p = 0.048). There were no significant differences in the serum MMP-9 concentrations or the ratios of MMP-9/TIMP-1 between asphyxiated neonates with and without neurological sequelae on the day after birth. Our preliminary study suggests that serum MMP-9 levels on birth day are important for predicting neurological prognosis of neonates with asphyxia.