Cholinergic Enhancement Research Articles

Galanin hyperinnervates surviving neurons of the human basal nucleus of meynert in dementias of alzheimer's and parkinson's disease: A hypothesis for the role of galanin in accentuating cholinergic dysfunction in dementia

This study summarizes the findings from postmortem examination of the brains of 22 control cases without neurological deficit, 12 cases of senile dementia of the Alzheimer type (SDAT), and nine cases of Parkinson's disease (three without signs of intellectual deterioration, four with dementia, and two atypical with dementia nonresponsive to L-dopa treatment). The aim of this study was to find the similarities and differences in galanin innervation of the cholinergic basal nucleus neurons in these dementing disorders as compared with controls. Immunocytochemistry with antibodies against galanin peptide and against choline acetyltransferase was applied on perfused brain preparations. Galanin peptide is present in the basal nucleus of Meynert neuron networks in the normal human brain: in local circuit neurons, in a number of galanin/cholinergic neurons, and in a feedback circuit via collaterals) that terminate upon the cholinergic neuronal somata and dendrites. Thus, peptide galanin circuits could function as powerful modulators of the activities of basal nucleus cholinergic neurons, both within the basal forebrain and in their wider projections to the neocortex and amygdala. As galanin has been shown to inhibit cholinergic activity, this galanin network could suppress the activity of cholinergic neurons. In SDAT, there is a primary loss of cholinergic neurons compounded by a secondary reaction of the remaining cholinergic neurons to the terminal degeneration in the cortex. Galanin networks demonstrate an inverse relationship to the cholinergic cell loss. Galanin axons hypertrophy and hyperinnervate the remaining cholinergic neurons. In Parkinson's disease the loss of cholinergic neurons is accentuated by the presence of dementia: the hypertrophy of the galanin axonal networks on cholinergic neurons is dramatic in Parkinson's disease with dementia. These observations throw new light on the neurotransmitter bases for these dementias. Galanin controls cholinergic mechanisms in the basal nucleus of Meynert, and dementia is accompanied by augmentation of galanin innervation onto an already depressed population of cholinergic neurons, thus demonstrating an appreciable amount of plasticity even in aged brain. These findings suggest that the present therapy of cholinergic enhancement as a means to retard intellectual deterioration can by itself have little effect at best, in these dementias. The suppressive effect of galanin peptide has to be reduced or curtailed, perhaps concurrently with the treatment of the cholinergic deficit.(ABSTRACT TRUNCATED AT 400 WORDS)

GROWTH HORMONE RESPONSES TO PYRIDOSTIGMINE IN NORMAL ADULTS AND IN NORMAL AND SHORT CHILDREN

There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholinesterases inhibitor, on GH release in normal adults (n = 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n = 7) or constitutional growth delay (n = 12) were studied. In SC the insulin hypoglycaemia (IH)-induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean +/- SEM 11.0 +/- 2.2 ng/ml in NC and 11.2 +/- 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 +/- 76.6 and 327.8 +/- 43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 +/- 1.1 ng/ml) which was significantly lower (P less than 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA:205.6 +/- 33.7 ng/ml/h, P less than 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 +/- 0.6 vs 16.4 +/- 1.9 ng/ml P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Muscarinic cholinergic enhancement of inositide turnover in cerebral nerve endings is not mediated by calcium uptake

Muscarinic cholinergic stimulation of rat cerebral nerve endings incubated with 32P i causes an enhancement of the labeling of phosphatidic acid (PA) and phosphatidylinositol (PI). The involvement of Ca 2+ in the stimulation of PA and PI labeling by carbamylcholine (CCh) was investigated. Enhancement of Ca 2+-influx with veratridine and the Ca 2+-ionophore A23187 caused a vast decrease of the labeling of the polyphosphoinositides, which was not accompanied by an enhancement of the labeling of PA and PI. The dihydropyridine Ca 2+-agonist BAY K 8644 did not affect phospholipid labeling. A23187, veratridine and BAY K 8644 did not enhance stimulation of the labeling of PA and PI by CCh. When Ca 2+ was omitted from the incubation, A23187 caused an enhancement of basal and CCh-stimulated labeling of PA and PI, possibly indicating a particular feature of A23187 unrelated to its iontophoretic properties. The Ca 2+-channel antagonists nimodipine, verapamil and flunarizine were virtually without effect on basal and CCh-stimulated labeling of PI and PA. These data support the notion that the muscarinic cholinergic inositide response is not mediated or controlled by Ca 2-flux.

Effects of cholinergic enhancement therapies on memory function in Alzheimer's disease: a meta-analysis of the literature.

A quantitative analysis of the literature on cholinergic enhancement of memory function in Alzheimer's disease showed that such therapies do have an effect if dosages are individualised. Treatments that combine a precursor with an anticholinesterase, however, appear to be the most promising for clinically useful results. The number of studies that have evaluated this combination treatment is small, but the present analysis indicates that further clinical trials would be most worthwhile.

Efficacy of oral physostigmine in primary degenerative dementia

To examine the efficacy of cholinergic enhancement in senile dementia of the Alzheimer type (SDAT), oral physostigmine was given to eight patients in a cross-over trial of three dose levels and a matching placebo. A dose-related improvement in memory as measured by objective verbal memory tests was observed. Performance was significantly better on the highest dose, 2 mg every 2 h, than on the lower doses. The effect was most systematically present for very short-term memory, which raises the question of whether the improvement may involve attention rather than longer term storage and retrieval.

Extracts of skeletal muscle increase neurite outgrowth and cholinergic activity of fetal rat spinal motor neurons.

A soluble extract of rat skeletal muscle increased neurite outgrowth and cholinergic activity of dissociated ventral spinal neurons in culture. The effects were concentration-dependent, saturable, and labile in the presence of heat or trypsin. The morphological enhancement was produced only by skeletal muscle extract and decreased with developmental age, whereas the cholinergic enhancement was produced by extracts of cerebral cortex and cardiac and skeletal muscle and did not change with age. These changes were specific for ventral cord neurons, but no species specificity was observed with respect to the muscle source or the neuronal target.

Septal transplant reinnervation of the hippocampus: Cholinergic enhancement of radial maze performance

The collateral sprouting of sympathetic axons following lesions to either the fimbria or medial septal nucleus was reported by Stenevi and Bjorklund in 1978. Since that time, a literature has developed on this phenomenon that Loy and Moore called anomalous sympathetic innervation (ASI). The cell bodies of the sprouting axons that supply this anomalous sympathetic innervation are located in the superior cervical ganglia of the sympathetic nervous system. These axons normally enter the brain along the carotid arteries and terminate in blood vessels in the brain. The superior cervical ganglia are surgically accessible and with some care can be removed, thus preventing the development of this anomalous innervation by eliminating the source of the sprouting axons. This chapter describes the possible effects of hippocampal lesions in several different experiments involving five behaviors: open field exploration, spontaneous alternation tendencies in a T-maze, acquisition of spatial maze pattern, latent learning of spatial maze patterns, and conditioned taste aversion to novel substances. Spontaneous alternation was evaluated by giving each rat three trials in an unbaited T-maze. The latter two trials constituted the test trials. If on trial two the rat entered the arm not entered on trial 1, then that was counted as an alternation. Similarly, if on trial three the rat entered the arm not entered on trial 2, then that was counted as an alternation.

Pineal cells enhance choline acetyltransferase activity in sympathetic neurons.

Cells derived from the neonatal rat pineal gland were cocultured with cells derived from neonatal rat superior cervical ganglia (SCG) in an attempt to determine whether a sympathetic target organ with only adrenergic properties could enhance the development of adrenergic transmitter properties in sympathetic neurons in tissue culture. Choline acetyltransferase was measured as an index of cholinergic differentiation, and tyrosine hydroxylase was measured as an index of adrenergic differentiation. As indices of total cell number and cellular volume, DNA and protein, respectively, were also measured. We found that the pineal-SCG cocultures contained ten times greater choline acetyltransferase activity than sister neuronal cultures cultured without pineal cells, thus indicating that the pineal cells enhanced cholinergic properties in the sympathetic neurons. This cholinergic enhancement was dependent upon the presence of nerve growth factor and could not be obtained with pineal-conditioned medium. Tyrosine hydroxylase activity, measured on cultures sister to those mentioned above, was low in all cultures and decreased somewhat in SCGs cultured alone. TH activity in the pineal-SCG cocultures, however, increased slightly. Some tyrosine hydroxylating activity developed in pineals cultured alone, however, and may have been responsible for the small increase in tyrosine hydroxylase activity noted in the pineal-SCG cocultures. The implications of these results for a determination of the role that target organ plays in the development of the transmitter properties of sympathetic neurons are discussed.

Meige disease

A dopamine agonist (apomorphine) and a cholinomimetic drug (physostigmine) were administered to five patients with blepharospasm and oromandibular dystonia (Meige disease). The effects of haloperidol and levodopa were also assessed. Apomorphine lessened and physostigmine aggravated the facial dyskinesias in all patients, while placebo injections had no consistent effect. Levodopa did not modify the symptoms, but haloperidol attentuated the facial dystonia. Dysfunction of the basal ganglia, characterized by a state of striatal dopamine preponderance, probably underlies the dystonic spasms in Meige disease. The prominent cholinergic enhancement of facial dyskinesias may distinguish this disorder pharmacologically from tardive dyskinesia, a differentiation which has practical therapeutic implications.

LES pressure response to pentagastrin: effect of cholinergic augmentation and inhibition.

Studies were performed on the anesthetized adult opossum to examine a) the pressure response of the lower esophageal sphincter (LES) to both bolus injections and continuous infusions of pentagastrin (PG), and b) how this response is affected by either cholinergic antagonism with atropine or cholinergic enhancement with edrophonium, an anticholinesterase. Both the bolus injection and the continuous infusion of PG produced dose-dependent rises in LES pressure. The peak pressure responses occurred at 1 microgram/kg and 32 microgram/kg-h, respectively. Atropine (100 microgram/kg), in a dose that significantly diminished the LES response to exogenous acetylcholine, had no significant effect on PG-induced increases in LES pressure. Similarly, edrophonium (100 microgram/kg) had no effect on the response of the LES to PG stimulation. The Sphincter's response to exogenous acetylcholine was significantly enhanced after edrophonium pretreatment. From these studied, we conclude that PG-induced increases in the LES pressure are due primarily to the direct stimulation of sphincter smooth muscle rather than to activation of excitatory cholinergic neurons.

Mediation of immunologic discharge of lysosomal enzymes from human neutrophils by guanosine 3',5'-monophosphate. Requirement of calcium, and inhibition by adenosine 3',5'-monophosphate.

The purpose of this investigation was to elucidate the relationship of cyclic GMP and calcium to the immunologic discharge of lysosomal enzymes from purified human neutrophils. Contact of neutrophils with a variety of immunologic stimuli, including zymosan particles treated with either normal or rheumatoid arthritic (RA) serum, heat-aggregated (agg) IgG, particulate and immobilized agg IgG each treated with RA serum, and zymosan-treated serum, provoked the discharge of beta-glucuronidase, but not cytoplasmic lactate dehydrogenase, and stimulated the accumulation of cyclic GMP. Both enzyme release and elevation of cyclic GMP levels required the presence of extracellular calcium as neither cellular event proceeded in its absence. Cholinergic enhancement of the immunologic secretion of beta-glucuronidase from neutrophils by acetylcholine was associated with a concomitant accumulation of cyclic GMP. These actions of acetylcholine on neutrophils did not proceed in the absence of extracellular calcium. Whereas the concentrations of cyclic GMP in neutrophils were elevated by both immune reactants and a combination of the latter and acetylcholine, cyclic AMP levels remained unaltered. Thus, cyclic GMP, but not cyclic AMP, was associated with the immunologic and pharmacologic discharge of lysosomal enzymes from neutrophils. Contrariwise, cyclic AMP, but not cyclic GMP, was associated with inhibition of lysosomal enzyme release. For example, dibutyryl cyclic AMP and epinephrine inhibited the release of beta-glucuronidase from neutrophils that was elicited by each of the immune reactants tested. Moreover, cyclic AMP levels in the cells were elevated markedly in every instance that enzyme discharge was inhibited by epinephrine. Epinephrine did not alter the neutrophil concentrations of cyclic GMP at times when those of cyclic AMP were elevated. The data in this report constitute partial evidence that the immunologic discharge of lysosomal enzymes from human neutrophils is mediated or signaled by intracellular cyclic GMP and that calcium is linked to this stimulation of enzyme secretion.