Chronic fluoride toxicity decreases the number of nicotinic acetylcholine receptors in rat brain

In order to investigate the molecular mechanism(s) underlying brain dysfunction caused by chronic fluorosis, neuronal nicotinic acetylcholine receptors (nAChRs) in the brain of rats receiving either 30 or 100 ppm fluoride in their drinking water for 7 months were analyzed in the present study employing ligand binding and Western blotting. There was a significant reduction in the number of [³H]epibatidine binding sites in the brain of rats exposed 100 ppm of fluoride, but no alteration after exposed to 30 ppm. On the other hand, the number of [¹²⁵I]-BTX binding sites was significantly decreased in the brains of rats exposed to both levels of fluoride. Western blotting revealed that the level of the nAChR 4 subunit protein in the brains of rats was significantly lowered by exposure to 100 ppm, but not 30 ppm fluoride; whereas the expression of the 7 subunit protein was significantly decreased by both levels of exposure. In contrast, there was no significant change in the level of the β2 subunit protein in the brains of rats administered fluoride. Since nAChRs play major roles in cognitive processes such as learning and memory, the decrease in the number of nAChRs caused by fluoride toxicity may be an important factor in the mechanism of brain dysfunction in the disorder.     

Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson's disease

Reductions in the number of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to occur in connection with Parkinson's disease (PD), but it is still unclear which subtype of this receptor is affected. In the present study we examined various nAChR subtypes employing ligand binding, as well as levels of subunit protein and mRNA in the brains of PD patients and age-matched controls. Binding of [3H]epibatidine and levels of alpha3 mRNA in the caudate nucleus and temporal cortex, but not in the hippocampus were significantly decreased in the PD brain. The level of the alpha3 protein subunit was significantly reduced in all these brain regions but there was no change in the level of alpha4. The level of the beta2 protein subunit in the temporal cortex and hippocampus and the beta2 mRNA in the temporal cortex was lowered. Both the levels of the alpha7 subunit protein and [125I]alpha-bungarotoxin binding were significantly increased in the temporal cortex of PD patients whereas the alpha7 mRNA level was unchanged. These findings reveal selective losses of the alpha3- and beta2-containing nAChRs and an increase in the alpha7 nAChRs that might be related to the pathogenesis of PD.     

Early diagnosis of Alzheimer disease with positron emission tomography

The emergence of drugs that may slow progression of Alzheimer disease, if administered early during its course, has necessitated early diagnosis of the disease itself. Among the functional imaging methods that could assist in early diagnosis, positron emission tomography has an important role in providing quantitative measures of various aspects of brain function affected by the disease. Positron emission tomography studies in patients with Alzheimer disease have revealed a typical pattern of metabolic deficits in the temporal and parietal lobes. Additionally, converging evidence from numerous studies indicates that a similar pattern of deficits can be observed in nondemented subjects who are at risk of developing the disease, such as those with recognized genetic traits such as familial Alzheimer disease with mutations in chromosomes 21 and 14, Down syndrome, subjects with the epsilon4 allele of the apolipoprotein E gene, and individuals with mild cognitive impairment. These findings might have implications for the selection of patients for clinical trials, defining the outcome measures and evaluation of treatment efficacy and responder characteristics, but should be confirmed by prospective studies comprising larger samples and include clinicopathologic correlations.     

Screening for minimal brain dysfunction (MBD/DAMP) at six years of age: results of motor test in relation to perinatal conditions, development and family situation

The aim of this study was to investigate if children aged 6 years of age, classified as having minimal brain dysfunction (MBD) or deficit in attention, motor control and perception (DAMP), exhibit special medical problems, specific developmental features or if special psychosocial conditions exist in the family. The screening program, using the psychoneurological part of the method developed by Gillberg et al., included 234 children who were followed-up prospectively from pregnancy and birth. The results were related to the physical and mental development of the children, to the psychosocial and socioeconomic conditions of the families, to pre- and postnatal conditions and to “reduced optimality score”, as defined by Prechtl. Mental development was assessed by the use of Griffiths' test at 10-14 months and at 4-5 years of age. At the second Griffiths' test, the mother was also interviewed about the presence of aggressiveness and other symptoms of childhood psychopathology in her child, as defined by the DSM-III criteria, and a psychological observation was also made. In addition to screening for MBD/DAMP, at 6 years of age the parents were asked to complete a questionnaire aimed at identifying attention deficit disorder (ADD). No medical or psychological intervention was made before this stage. Fourteen children (9M, 5F) (6%) were identified as having a positive MBD/DAMP screening result. The results of the screening procedure showed a weak correlation with those obtained using the questionnaire based on the DSM-III criteria for ADD. Compared with the rest of the children, those with a positive MBD/DAMP screening result had an increased number of complications during pregnancy but not a reduced optimality score. At 4 years of age the performance on the Griffiths' test was lower and the rate of child psychiatric symptoms such as aggressiveness and signs of the mother having difficulties in setting limits for the child were more common than among the rest of the cohort. No relation was found with the psychosocial or socioeconomic conditions of the family. We conclude that children suspected of having MBD/DAMP at the start of school may have exhibited signs of delayed psychoneurological development and symptoms of psychopathology at 4 years of age.     

Effect of long-term nicotine treatment on [3H]nicotine binding sites in the rats brain

Male rats were receiving nicotine (base), 50 mg/kg in their drinking fluid for 9 and 41 weeks, respectively. A markedly reduced intake of fluid was observed during both regimes of nicotine treatment. At withdrawal of nicotine after 9 weeks of treatment the intake of water was immediately increased up to control level while in rats with 41 weeks of exposure the intake of drinking fluid increased to 65% over the control level still 14 days after withdrawal of nicotine. Tolerance to nicotine was measured after 7 days of abstinence in rats treated for 9 weeks. No significant change in cholineacetyltransferase (ChAT) activity or number of muscarinic binding sites in brain was observed after 9 or 41 weeks of nicotine treatment. Twenty-four hours after withdrawal from the 41 weeks nicotine treatment there was a significant increase of 46% in the number of [3H] nicotine binding sites in the hippocampus while the number of binding sites was decreased by 44% in the cortex and unchanged in the midbrain. On day 14th of abstinence these changes had disappeared. Following 9 weeks of nicotine treatment no change in [3H] nicotine binding was observed after 24 h or 7 days of abstinence.     

Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor

Purpose The purpose of this study was to analyse whether non-radiolabelled epidermal growth factor (EGF) can modify the cellular uptake of ¹²⁵I when delivered as [¹²⁵I]trastuzumab. ¹²⁵I was used as a marker for the diagnostically and therapeutically more interesting isotopes ¹²³I (SPECT), ¹²⁴I (PET) and ¹³¹I (therapy).Methods The cell-associated radioactivity was measured in squamous carcinoma A431 cells following addition of [¹²⁵I]trastuzumab. Different concentrations of [¹²⁵I]trastuzumab and unlabelled EGF were used, and the total, membrane-bound and internalised radioactivity was measured. We also analysed how EGF and trastuzumab affected the cell growth. Results It was generally found that the cellular ¹²⁵I uptake was decreased by the addition of EGF when [¹²⁵I]trastuzumab was added for short incubation times. However, if the incubation times were longer, EGF increased the ¹²⁵I uptake. This shift came earlier when higher [¹²⁵I]trastuzumab concentrations were applied. The addition of EGF also influenced cell proliferation, and concentrations above 10 ng/ml reduced cell growth by approximately 20% after 24 h of incubation.Conclusion By adding unlabelled EGF, it was possible to modify the cellular uptake of [¹²⁵I]trastuzumab. This points towards new approaches for the modification of radionuclide uptake in EGFR- and HER2-positive tumours.