Maria Sandra Magnoni

The aging brain: Protein phosphorylation as a target of changes in neuronal function

There is evidence that senescence affects neurotransmission at different levels. In particular, this review summarizes the studies on age-dependent modifications in protein phosphorylation, which represents the final pathway in the action of transmitters and hormones at neuronal level. Cyclic AMP-dependent protein kinase and protein kinase C have been reported to be modified during aging in various cerebral areas; the changes may involve either enzyme activity or substrate availability. These findings can be related to the alterations in neurotransmitter function and synaptic efficiency observed in the senescent brain. The activity of the other types of protein kinases (tyrosine-, cGMP-, calcium/calmodulin-dependent) during aging needs to be explored. An emerging point is the role of protein phosphorylation in the transfer of membrane signals to the nucleus, for the activation or disactivation of specific genes responsible for long-term neuronal events. Along this view, alterations in protein kinase pathway during senescence would ultimately affect gene expression, resulting in long term modifications of cell function. The reviewed literature opens the perspective of restoring some of the deficits associated with senescence by modulating protein phosphorylation pathway.

β-adrenergic receptors in brain microvessels of diabetic rats

A significant decrease in the number of beta-adrenergic receptors was observed in cerebral microvessels of fatty (fa/fa) and streptozotocin-induced diabetic rats, without receptor affinity changes. These results suggest that alterations of central adrenergic regulation of small vessels may be involved in brain microvasculature disturbances that occur with diabetes.

L-Type Calcium Channels are Modified in Rat Hippocampus by Short-Term Experimental Ischemia

Increasing evidence suggests a role for calcium ions in the pathophysiology of ischemic brain damage. The major mechanism allowing calcium entry from the extracellular compartment is the opening of voltage-operated calcium channels. In this line, we have explored the hypothesis that the characteristics of central L-type voltage-dependent calcium channels, labeled by the dihydropyridine ligand 3H-PN 200-110, may be modified by experimental ischemia. The results show that short-term mild ischemia, produced in the rat by 1 h of right carotid ligation, induces an increase in the number of 3H-PN 200-110 binding sites in the hippocampus ipsilateral to the side of carotid occlusion, accompanied by an increase in the dissociation constant value, whereas no changes in the kinetic parameters of the binding were observed in the other areas examined, i.e., the cortex and the striatum. The changes in hippocampus are transient: 96 h after the occlusion, binding parameters return to the control range. The modifications of the binding characteristics in the hippocampus may be related to alterations of Ca2+ fluxes through L-type calcium channels.

Angiotensin-Converting Enzyme Activity Is Reduced in Brain Microvessels of Spontaneously Hypertensive Rats

Abstract: Angiotensin‐converting enzyme (ACE) activity in brain microvessels of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls was measured. Cerebral microvessels, prepared from the cerebral cortices by the albumin flotation and glass bead filtration technique, were free of neuronal and glial elements. ACE activity in brain microvessels of SHR was lower than that of WKY. A Woolf‐Augustinsson‐Hofstee plot showed that the reduction of the enzyme activity in SHR was due to a 30% decrease in Vmax without any change in Km for substrate. The decrease of ACE activity in brain micro‐vessels of SHR may indicate an impairment of the central renin‐angiotensin system and may be related to cerebral microvascular dysfunctions occurring in hypertension.

The Central Dopaminergic System: Susceptibility to Risk Factors for Accelerated Aging

The synaptic deficit of brain dopaminergic activity involves a complex pattern of changes both at presynaptic and at postsynaptic level. The aged dopaminergic nuclei present a reduced number of dopamine terminals, a decreased ability to synthesize and reuptake dopamine and defective recognition sites both in terms of absolute number of D2 receptors and of transducing mechanisms linked to D1 receptors. These changes suggest that the dopaminergic system may be particularly sensitive during aging to environmental, iatrogenic and toxic factors, which may easily make the elderly develop symptoms of central dopamine deficiency.

Effect of common carotid occlusion on beta-adrenergic receptor function in cerebral microvessels.

beta-adrenergic receptors were measured in cerebral microvessels of gerbils and rats after ligature of the right or left common carotid artery. The results indicate a decrease in the number of beta-adrenergic receptors in brain microvessels of both ipsilateral and contralateral hemispheres. This event may reflect altered patterns of the neuronal regulation of brain microvasculature and may be related to cerebrovascular alterations which are concomitant with ischemia. Furthermore, the results show that the decrease in beta-receptor density is more pronounced in the left hemisphere, independently on the side of carotid occlusion. This finding suggests that microvessel function in the left side of the brain is more vulnerable to hypoxia effects.

Time-related asymmetric changes of brain microvessel beta-adrenergic receptors in the two hemispheres after carotid occlusion.

The effect of short term and long term ischemia induced by right carotid occlusion was studied on beta-adrenergic receptor function in rat cerebral microvessels. The results show a different time-dependent responsiveness of the two hemispheres to ischemia, with a pronounced and more persistent decrease in the number of capillary beta-receptors in the left side of the brain. The data suggest the existence of asymmetries in the control of brain microvasculature which may mediate the different time-course of beta-receptor changes in response to ischemia.

Regulatory Mechanisms of Neuron to Vessel Communication in the Brain

The highest level of integrative brain function requires the existence of homeostatic mechanisms aimed to the maintenance of the internal cerebral milieu. In fact, marked fluctuations in the extracellular fluid concentration of neurotransmitters, amino acids, hormones, nutrients, ions, can interfere with the neuronal processes, which are dependent on the chemical composition of the cerebral microenvironment. For example, significant changes in K+ concentration can adversely affect neuronal activity, and trigger a cascade of events which may ultimately be deleterious for the cell. The evolution in parallel of the high level of cerebral integrative processes and the efficiency of dynamic mechanisms for the regulation of brain milieu is supportive of the hypothesis that homeostasis and isolation are the principles that ensure a correct brain function.

Glial Brain Tumors Lack Microvascular Adrenergic Receptors

In human and animal brain microvessels beta-adrenergic receptors have been identified which are suggested to subserve the regulation of capillary function in both physiological and pathological conditions. Brain tumors are supplied by vessels that differ from those supplying normal cerebral tissue in various structural and functional parameters. In order to study the characteristics of brain tumor microcirculation, we have investigated the presence of beta-adrenergic receptors in capillaries isolated from different types of neoplasms using the specific radioligand 125I-iodocyanopindolol (ICYP). The microvessels were isolated and prepared by albumin flotation and glass bead filtration from normal and pathological tissues. No ICYP-specific binding was detected in the microvessels of tumors of glial origin, while capillaries obtained from meningiomas and neurinomas showed, like the normal brain, a specific binding of the radioligand. The data indicate that the regulation of capillary function in glial tumors differs from that of normal cerebral tissue and extraparenchymal tumors, thus indicating an impaired control of the vascular permeability.

Partial reversal of asymmetry in microvessel neurochemical changes after ischemia by corpus callosum section.

Common carotid occlusion in the rat significantly decreases the density of beta-adrenergic receptors in preparations of microvessels obtained from ipsilateral and contralateral cerebral cortices. The disruption of nerve pathways connecting the hemispheres (callosal transection) partially reverses the effect of common carotid occlusion on beta-adrenergic receptor density in capillaries of the contralateral cortex. In addition, the destruction of the central noradrenergic system by intraventricular injection of 6-hydroxydopamine abolishes the effect of ischemia on capillary beta-adrenergic receptor function in both hemispheres. The results suggest that beta-adrenergic receptors located on microvessels are partially regulated by neuronal pathways and that focal ischemia induces neurochemical and functional changes in remote areas of the brain.