Mechanism of axonal transport: a proposed role for calcium ions.

In vitro axonal transport of tritiated protein decreased 40 to 60 percent when neuronal cell bodies were incubated in calcium-free medium, but was not affected when only nerve trunks were exposed to calcium-free conditions. In addition, calcium-45 was transported along axons at a rate similar to that of rapidly transported tritiated protein. These data are interpreted to suggest that calcium ions are involved in the initiation of axonal transport and in the coupling of transported proteins to the transport system.

Centrally acting alpha 1-adrenoceptor agonists based on hexahydronaphth[2,3-b]-1,4-oxazines and octahydrobenzo[g]quinolines.

Centrally acting alpha 1-agonists may be of therapeutic value in dementias and other CNS disorders characterized by symptoms of noradrenergic insufficiency. Therefore, on the basis of known peripherally acting alpha 1-agonists two new groups of centrally acting alpha 1-agonists with improved lipophilicity, the hexahydronaphth[2,3-b]-1,4-oxazines type A and the octahydrobenzo[g]quinolines type B were designed. The N-methylated derivatives 14 and 33 demonstrate potent, direct agonistic activity at postjunctional alpha 1-receptors. Ring substituent alterations in compounds of type A and B change the potency of compounds on the rabbit ear artery by over 3 orders of magnitude (pD2 = 5.35-8.40). The efficacy of these compounds varies from 42 to 110%. Those alpha 1-agonists which were selective in the pithed rat increase vigilance in rats. Compound 14 was found to be a centrally acting alpha 1-agonist with good tolerability in different animal species and in healthy volunteers. Furthermore, 14 selectively stimulates the breakdown of phosphatidylinositol in rat cerebral cortex slices. In vivo, the compound reverses behavioral deficits in animals which received noradrenergic lesions following DDC or DPS4 treatment. Oxazine 14 and its close derivatives are by far more lipophilic than commonly known alpha 1-agonists. This is demonstrated in a ClogP-PROBIS plot.

Recovery of choline acetyltransferase and acetylcholinesterase activities in the ipsilateral hippocampus following unilateral, partial transection of the fimbria in rats.

An initial decrement followed by a significant recovery of choline acetyltransferase and acetylcholinesterase activities in the ipsilateral hippocampus was observed in rats with unilateral, partial transection of the fimbria. Regeneration of hippocampal cholinergic terminals could account for the parallel return towards normal of both the enzyme activities. We suggest that the still intact fimbrial fibres, homologous to those severed, contribute to the observed recovery.

Recovery of enzyme markers for cholinergic terminals in septo-temporal regions of the hippocampus following selective fimbrial lesions in adult rats.

The activities of choline actyltransferase and acetylcholinesterase were determined in five consecutive septo-temporal regions of the ipsilateral and contralateral hippocampus from unlesioned controls and lesioned animals at various times following lateral, medial or complete unilateral transection of the fimbrial bundle in rats. In control animals distribution of cholinergic enzymes suggests a relatively heavier innervation of the ventral hippocampus. In lesioned animals depletion of enzyme activities in septo-temporal regions of the ipsilateral hippocampus was consonant with the known topography of cholinergic innervation of the hippocampus via the dorsal and ventral pathways. After 4 and 8 week post-lesion survival, a substantial recovery of both enzyme activities was evident following either of the lesion paradigms employed. However, the extent and the pattern of enzyme restitution depended on the type of fimbrial transection and the hippocampal region under consideration. Significant enzyme alterations were also observed in the contralateral hippocampus following all three lesion types. We interpret the lesion-induced temporal consequences in cholinergic enzymes to indicate initial degeneration and subsequent regeneration of cholinergic terminals in the hippocampus. The present findings also suggest that homologous fimbrial fibres spared by the partial lesions are responsible for the ensuing recovery. Thus, partial lesions of well-defined efferents constitute a suitable experimental paradigm to demonstrate homotypic reconstruction in the adult mammalian central nervous system.

Homologous cholinergic efferents spared by partial fimbrial lesions contribute to the recovery of hippocampal cholinergic enzymes in adult rats.

Cholinergic fibers spared by partial lesions of the fimbrial bundle contribute to the recovery of enzyme markers for hippocampal cholinergic terminals. This recovery, most likely representing structural restoration of cholinergic terminals lost to lesion-induced degeneration, is amplified by a 'conditioning' lesion. This model of functionally relevant postlesion reconstruction, by and of structures within the CNS, is suitable to search for means to enhance homotypic collateral sprouting.

Time course of the elevation of nerve growth factor (NGF) content in the hippocampus and septum following lesions of the septohippocampal pathway in rats.

Axotomy of cholinergic neurons in the medial septum-diagonal band and degeneration of their terminals in the hippocampus resulting from fornix-fimbria lesions induce elevation of NGF content in these two brain regions. Postlesion levels of cholinergic neuron-specific ChAT activity in the septum suggest that endogenously produced NGF may, at least partly, promote survival of axotomized cholinergic neurons or induce ChAT activity in undamaged cells or both. These findings thus support the proposed trophic role for NGF in central cholinergic neurons.

Fimbria-fornix lesion increases nerve growth factor content in adult rat septum and hippocampus.

Bilateral complete transection of the fimbria-fornix causes a significant increase in nerve growth factor (NGF) content both in the septum and hippocampus of the adult rat as measured by a sensitive immunoassay 7 days after lesioning. The finding, that elevation of NGF in septum (250%) was much more pronounced than that in the hippocampus (30-50%), cannot be explained by retrograde axonal transport. Degeneration of central cholinergic neurons might be a potential trigger for NGF production in the CNS.

Deficits in cholinergic enzymes and muscarinic receptors in the hippocampus and striatum of senescent rats: effect of chronic hydergine treatment.

Choline acetyltransferase and acetylcholine esterase activities in the hippocampus and striatum were significantly decreased in senescent (26-36 mo.) rats as compared with adult (11-12 mo.) animals. A significant reduction in 3H-QNB binding sites was also observed in the striatum from aged rats whereas in the hippocampus these binding sites were not influenced by age. A four week treatment of aged animals with Hydergine resulted in an increase in choline acetyltransferase activity so that the age-dependent deficit was no longer apparent.

Deficits in cholinergic enzyme activities in septo-temporal regions of the senescent rat hippocampus, and in the forebrain of aged mice: effect of chronic Hydergine treatment.

Choline acetyltransferase and acetylcholinesterase activities in the septo-temporal regions of the rat hippocampus, and in the forebrain of mice were significantly decreased in senescent as compared with adult animals. A four week treatment of aged rats or mice with Hydergine resulted in the restoration of choline acetyltransferase activity.

Noradrenergic, serotonergic, and cholinergic sprouting in the hippocampus that follows partial or complete transection of the septohippocampal pathway: contributions of spared inputs.

The aminergic and cholinergic fibers innervating the hippocampus reach their target regions via the dorsal (dorsal fornix, fimbria, and cingulum) and ventral routes. The plasticity of this innervation after lesions of the dorsal pathway was investigated in the septal, medial, and temporal regions of the adult rat hippocampus. The extent and time course of sprouting was assessed by determining high-affinity uptake of [3H]noradrenaline and [3H]serotonin, and the activities of cholinergic enzymes 1 week to 6 months after partial or complete transection of the dorsal pathway. The initial decline in these terminal indices resulting from the transection of the medial or lateral half of the dorsal pathway reflected the distribution of their respective terminal sites in the three hippocampal regions. Longer survival after such lesions led to a substantial recovery of cholinergic and noradrenergic markers indicating reinnervation of the hippocampus by spared dorsal and/or by undamaged ventral afferent fibers. Whether the recovery was complete or not, the sprouting of spared dorsal fibers was maximum within a relatively shorter postlesion survival whereas that of the ventral afferents continued for a longer time. In contrast to the extent of noradrenergic and cholinergic restitution, very poor serotonergic recovery was seen in the same animal in spite of the availability of spared serotonergic afferent fibers and regardless of the duration of postlesion survival. The apparently finite capacity of spared axons for postlesion reinnervation was not increased by longer survival. Amplification of this property of central neurons by other interventions may supplement the approach of transplantation for recovery of function following injury.