Biomedical subjects
Publications and source records attributed to I Hanin.
A diurnal oscillation of acetylcholine concentrations in rat brain has been demonstrated by gas chromatography. Peak concentrations occur at 2 hours of light, and a trough is seen at 6 hours of darkness. This pattern is observed only in grouped rats, and emerges after at least 18 days of prior conditioning in an environment with controlled light, humidity, and temperature.
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The cholinergic neurotoxin AF64A (ethylcholine aziridinium) has been used to selectively destroy the cholinergic system. Due to its structural similarity to choline, this compound may be selectively taken up by the cholinergic terminal via the high-affinity choline transport (HAChT) system to produce persistent and selective cholinergic deficits. The mechanism by which it exerts its cholinotoxicity remains to be elucidated. We have examined the effects of AF64A in the human neuroblastoma cell line, LA-N-2, which has an intact sodium-coupled choline uptake system, and is capable of synthesizing acetylcholine (ACh). AF64A (25, 50 and 100 microM) produced dose-dependent increases in cell kill as measured by colony formation assay. The addition of increasing concentrations (10(-5), 10(-4) and 10(-3) M) of choline and hemicholinium-3 (HC-3) protected the cells from the cytotoxic effects of AF64A. At the same doses, AF64A also decreased choline acetyltransferase (ChAT) activity. In the presence of the highest concentration of choline or HC-3 (10(-3) M) which produced complete protection against AF64A's cytotoxicity in the colony formation assay, ChAT activity was restored to control values. These results demonstrate that agents that utilize (i.e., choline) or inhibit (i.e., HC-3) the choline uptake system prevented AF64A-induced cytotoxicity and decreases in ChAT activity, in a manner similar to that which has been observed in chick and rat primary cholinergic cultures in vitro. The LA-N-2 neuroblastoma cell line thus serves well as an in vitro model of the cholinergic neuron and provides a useful system to study the mode of cholinotoxicity induced by AF64A.
High molecular weight glycosaminoglycans (GAG) and proteoglycans (PG) affect pathological changes of the brain in Alzheimer's disease (AD). PG stimulate the processing and aggregation of amyloid-beta (Abeta), protect the protein from proteolysis, and increase the formation of neurofibrillary tangles by inducing the hyperphosphorylation of tau protein. These effects may be competitively inhibited by GAG. We have studied the effects of orally (by gavage) and subcutaneously (s.c.) administered low molecular weight heparin, C3 (4-10 oligosaccharides; MW = 2.1 kDa; USP value = 12 U/mg), on abnormal tau-2 protein immunoreactivity in the rat hippocampus following a single, unilateral intra-amygdaloid administration of Abeta(25-35). Oral administration of C3 (25 mg/kg; once daily) was initiated 3 days prior to Abeta(25-35) administration, and was continued daily for an additional 14 days. S.c. administration of C3 (2.5 mg/kg, twice daily), was started 3 days prior to, and was continued for 32 days after, Abeta(25-35) administration. Animal brains were subsequently processed for tau-2, ChAT-immunoreactivity, choline acetyltransferase (ChAT) activity and acetylcholinesterase (AChE) activity. Both oral and s.c. administration of C3 attenuated Abeta(25-35) induced appearance of tau-2-immunoreactive (IR) perikarya in the ipsilateral hippocampus (P < 0.05). Hippocampal cholinergic enzyme activity in C3 treated animals was not significantly different from control animals. The present findings suggest that C3 might be used successfully to prevent abnormal tau protein formation in chronic neurologic diseases, such as AD. Moreover, our data demonstrate that the mechanism of this effect does not appear to influence the cholinergic system of the brain.
Alzheimer's disease (AD) literature indicates that glycosaminoglycans (GAGs) may prevent proteoglycan-induced amyloid-beta (Abeta) aggregation, decrease Abeta-induced tau-2 immunoreactivity, and increase the axonal growth and arborization of hippocampal neurons. However, there is no information about the impact of GAGs on cholinergic lesions. Here, AF64A was administered stereotaxically into the lateral ventricles of rats, at doses that are selective for cholinotoxicity (1 and 2 nmol). The heparin-derived oligosaccharide (HDO), C3 (25mg/kg), was administered orally, once daily for 7 days before, and 7 days after AF64A administration. Choline acetyltransferase (ChAT) immunohistochemistry revealed that C3 administration reduced AF64A-induced cholinergic damage in the septum and cingulum bundle. Quantitative neuronal cell counts showed that C3 attenuated, by 60%, the decrease in cell number in the medial septum. Enzyme analysis showed that C3 also significantly restored ChAT (30%) and acetylcholinesterase (AChE) enzyme activity (45%), which had been diminished by AF64A. Our data suggest that, in addition to its effects of anti-Abeta aggregation, anti-Abeta-induced tau-2 immunoreactivity, and neurotrophic effects, C3 also effectively reduces AF64A-induced cholinergic damage; hence it may have potential therapeutic value in AD patients.