What is already known about this topic? An increasing number of studies have projected temperature-related mortality, but few consider the change of population’s adaptability to future temperature and mortality burden from cold and heat effects. What is added by this report? This study offers a comprehensive characterization of human adaptability and excess mortality burden of temperature across various regions of China. What are the implications for public health practice? The temperature-related excess mortality was projected to increase in the 2050s and decrease in the 2080s. Heat adaptability was projected to increase in the future, but along with the rising temperatures, the heat-related excess mortality continuously rose, except for the low-speed rising scenario. Although the excess mortality of cold was projected to decrease in the nearer future, it might not keep declining in the long run, due to the decreasing cold-adaptability, which deserves more attention.

This chapter discusses the neurochemical and behavioral studies on L-dopa toxicity in the model of manganese kesioned nigrostriatal pathway in the rat. Evidence was obtained with in vitro studies of a toxic action of L-dopa on neuroblastoma cells, evaluated as [3H]-thymidine uptake and cell survival. It was found that the chronic administration of L-dopa to normal adult rats or mice did not lead to nigral cell disappearance and did not endanger the survival of foetal ventral mesencephalic grafts inplanted in 6-OHDA lesioned striatum. Accordingly, studies performed on humans did not give evidence of the histological signs of L-dopa toxicity in normal subjects or in Parkinsonian patients. However, some clinical trials suggest that the wearing-off phenomenon, tardive dyskinesia, and on–off phenomena are the possible side effects of long-term L-dopa treatment. Apart from human studies, experiments on the in vivo toxicity of L-dopa were performed in unlesioned mice or rats and on foetal grafts in 6-OHDA lesioned rats suggesting a lack of any effect of L-dopa chronic administration on cell survival.

Publisher Summary This chapter describes the morphological and functional adaptation of basal ganglia neurons after cerebral ischemia. A series of neurological and behavioral impairments have been associated with brain injury that follows spontaneous or experimental cerebral ischemia. In 1979, a procedure—the 4-vessel occlusion method—of transient forebrain ischemia in the rat was proposed as a model of cardiac arrest. Reproducible focal neuronal damage in the dorsolateral part of the striatum as well as in various tele-diencephalic areas was obtained with this method. Recently, another reliable method for the induction of striatal ischemic damage in rats was obtained by local injection of endothelin-1 (ET-1), a potent vasoconstrictor agent. The hypoxicischemic damage induced by these procedures differently affects the various cell populations of the brain, in particular neurons. The chapter summarizes some of the results obtained by studying morphological and functional recovery after ischemic striatal injury induced by the 4-vessel occlusion or ET-1 intrastriatal injection in the rat.

This chapter describes the new morphological and functional features of fibroblast growth factor-2 (FGF-2) and gangliosides in the basal ganglia, especially in relation to the nigrostriatal dopamine system, which is degenerated in Parkinson's disease. The mapping of FGF-2 IR demonstrates an astroglial and neuronal localization within the substantia nigra and the globus pallidus, while in the neostriatum, the FGF-2 IR is confined to the astroglial populations. In the postnatal period, all areas of the basal ganglia including substantia nigra contained neuronal but not glial FGF-2 IR. In contrast to the adult rat, also a nuclear localization of FGF-2 IR can be observed within the nerve cells. In adulthood, the nuclear localization of FGF-2 IR is not seen in most neurons with the present antiserum but mainly in the astroglial cell populations. The FGF-2 IR DA nerve cells demonstrates within the zona compacta of the substantia nigra also a codistribution with the ganglioside positive nerve terminals, with high and low affinity FGF receptors and with FGF-2 mRNA level.

Numerical changes in the overall neostriatal neuronal population have been investigated by morphometric analysis of Nissl-stained and glucocorticoid receptor-immunoreactive neurons. Number and staining intensity of various chemically-identified nerve cell populations were analysed by means of immunocytochemistry coupled with computer-assisted image analysis. Three- and 24-month-old male Sprague-Dawley rats were used. No change in the number of Nissl-stained, glucocorticoid receptor-, dopamine and adenosine 3′:5′-monophosphate-regulated phosphoprotein- and enkephalin-immunoreactive neurons and a 50% decrease of neuropeptide Y-immunoreactive neurons were observed in the aged rat. In our preparations, the glucocorticoid receptor antibody stains around 90% of the neostriatal neurons, the dopamine and adenosine 3′:5′-monophosphate-regulated phosphoprotein and enkephalin antibodies label 25–35% and the neuropeptide Y antibody stains only 1% of neostriatal neurons. In the same preparations a significant decrease in the intensity of immunostaining was observed for enkephalin-, dopamine and adenosine 3′:5′-monophosphate-regulated phosphoprotein- and neuropeptide Y-immunoreactive neuronal cell bodies and tyrosine hydroxylase-immunoreactive nerve terminals in the aged rat. In the case of neuropeptide Y- and dopamine and adenosine 3′:5′-monophosphate-regulated phosphoprotein-immunoreactive neurons, the changes in the intensity of immunostaining were differentially compartmentalized within neostriatum, suggesting selective vulnerability of striatal subregions to ageing processes. In conclusion, these data indicate that no significant age-related neuronal cell loss occurs in neostriatum. On the other hand, a generalized decrease in the levels of peptide transmitters and molecules related to dopamine transmission is observed in aged rat neostriatum, possibly resulting in the known age-related deficits of neostriatally-controlled behaviours.

BACKGROUND AND PURPOSE:Transient forebrain ischemia induced in rats by the four-vessel occlusion method is known to produce severe neural damage in the hippocampus and striatum and a behavioral syndrome the major symptom of which is a working memory deficit. Recent evidence suggests that monosialogangliosides can ameliorate postischemic symptoms. Our purpose was to study the effect of siagoside, the inner ester of GM1 ganglioside, on some behavioral and morphological impairments induced by four-vessel occlusion in rats. METHODS:Rats were injected daily with 5 mg/kg i.p. siagoside starting 4 hours after the cerebral ischemia. After 14 days the rats were tested for working memory in a water T maze or scored for apomorphine-induced stereotypy. The rats were killed 21 days after the cerebral ischemia. Histological and computer-assisted morphometric analyses were performed on cresyl violet-stained brain sections, which were graded according to a neuropathologic score, and on sections stained with a monoclonal antiserum against dopamine and cyclic adenosine-3',5'-monophosphate-regulated phosphoprotein, a marker for striatal dopaminoceptive neurons. RESULTS:Siagoside treatment reduced the stereotypy score induced by low doses of apomorphine and the extent of striatal lesions but did not affect the working memory deficit or the extent of hippocampal lesions. CONCLUSION:Daily siagoside treatment after acute cerebral ischemia attenuates some morphological and functional deficits related to striatal damage. These effects can be interpreted as a selective protective action on striatal neural populations or as a modulatory action on neural systems involved in striatal control. These data are consistent with preliminary clinical reports showing that monosialogangliosides enhance motor recovery after acute ischemic stroke.

In reviewing a complex and multifaceted research subject, such as the ganglioside field, one may follow three different approaches, which can be exemplified by an analogy taken from literature. A writer can express a theme in a set of loosely related tales as Maupassant did; he can use a frame, into which tales are inserted, as in Boccaccio’s Decamerone; or he can organize the entire material into a single novel, characterized by a leitmotiv, as Dostoyevski did in his masterpiece The Brothers Karamazov. While reading papers on gangliosides and trying to review the work done in this field, we have the clear impression that it is impossible to organize it into a single story and that tales seem to be more appropriate to describe this subject.

The disposition of labelled [3H]GM1lactone, the inner ester of ganglioside GM1, was studied in the rat. After i.v. administration [3H]GM1lactone was quickly converted to its corresponding open form most likely by plasma esterases, and then displayed a pharmacokinetic profile identical to [3H]GM1. Following intramuscular administration of [3H]GM1lactone [3H]GM1 levels in plasma and in tissues were higher than those obtained after the administration of an equivalent dose of [3H]GM1. This increased bioavailability means that GM1lactone can be considered as a potential prodrug of GM1.

Intravenous injection of lysophosphatidylserine (2.5-25 mg/kg) increases the blood histamine level in mice. Lysophosphatidyl-D-serine, alkyl-lysophosphatidylserine and glycerophosphorylserine show little or no activity. As shown by the similar efficacy of the analogue lacking the OH group in the C-2 position of glycerol conversion into phosphatidylserine is not required. The age of mice influences the activity of lysophosphatidylserine. Thus, the increase in blood histamine is greater in adult mice (8-10 weeks) than in young mice (4-6 weeks). In old mice (50-60 weeks) the tolerance to lysophosphatidylserine is reduced. Repeated parenteral administrations induce depletion of histamine stores with concomitant desensitization to lysophosphatidylserine. Well-perfused organs containing connective tissue mast cells (tongue) are more affected. When [3H] histidine is injected into lysophosphatidylserine-treated mice, the highly radioactive histamine detected in the tongue indicates the preservation of histidine decarboxylase activity after degranulation. The data suggest that lysophosphatidylserine specifically activates connective tissue mast cells in mice.

Hippocampal cell loss during aging has been related to the toxic effects of corticosterone on this cell population. It is not known which receptor mediates corticosterone cytotoxicity. At least two types of receptors for corticosterone have been recognized in the rat brain, type I (corticosterone preferring receptor, CR) and type II (glucocorticoid receptor, GR). In the present study the possible changes in GR immunoreactivity (IR) in various tel- and diencephalic regions of the aged rat have been investigated using immunocytochemistry coupled with computer-assisted image analysis. Male Sprague-Dawley rats of 3, 12 and 24 months of age were used (n = 5/group). A selective decrease of GR-IR was observed in the CA1 hippocampal field and central amygdaloid nucleus of the 24-month-old with respect to both 3- and 12-month-old rats. While in the former region GR-IR decrease was paralleled by a decrease of IR field area, no age-related decrease of GR-IR profile number was detected in central amygdaloid nucleus. A significant decrease of GR-IR and IR field area was also observed in the dentate gyrus of 24- vs 12-month-old rats but not vs 3-month-old rats. The analysis of adjacent sections stained with Cresyl violet showed a pattern of age-related changes (decrease of neuronal profiles in CA1 field pyramidal layer and dentate gyrus granular layer, and no change in the central amygdaloid nucleus of aged rats) which paralleled the observed changes in GR-IR in the same areas. This study provides evidence that GR are selectively decreased in the hippocampal formation and in the central amygdaloid nucleus of the aged rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Today we understand the brain as a dynamic, not static, organ. Central nervous system (CNS) neurons are endowed with the capacity to react to chemical signals presented from their microenvironment with morpho-functional modifications, a process termed plasticity. This phenomenon has provided the foundation for studies directed at elucidating the pathophysiological correlates of neuronal life and death, with the ultimate objective of developing strategies to improve neurological outcome following various types of CNS insults, in particular cerebrovascular insufficiency (stroke), head and spinal trauma, and neurodegenerative diseases.

The present study was designed to investigate the turnover rates of D1 dopamine receptors in the brain and retina of adult and aged rats. To this aim, we monitored the increase in the density of H-3-SCH 23390 binding sites after the administration of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2 dihydroquinoline (EEDQ).The results indicate that, in aged rats, the production rate of D1 receptors decreases by 41% to 61% in the striatum, nucleus accumbens and substantia nigra, whereas a smaller reduction in the degradation rate of these receptors is observed (-21% to -40%). In contrast, the production rate of D1 receptors in the retina of aged rats remains unchanged, whilst the degradation rate decreases by 25%. These alterations in the rates of receptor production and degradation may account for the age-related decrease in the density of D1 dopamine receptors in the striatum, nucleus accumbens and substantia nigra as well as for the increase in the density of these receptors in the retina of aged rats.

Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) have been described to exert neuronotrophic effects on central nervous system neurons in culture. To study the selectivity of trophic actions of these growth factors, neurotransmitter-identified populations of embryonic rat mesencephalon were used. At 20 days in vitro, EGF (3 ng/ml) promoted survival and neurite outgrowth from these neurons. The neuritogenic effect of bFGF (3 ng/ml) was, however, more robust. Quantitative analysis with the neurofilament monoclonal antibody RT97 and ELISA confirmed the differential response, bFGF being 2-2.5 times more effective at all concentrations tested (ED100:3-10 ng/ml for both EGF and bFGF). At 10 days in vitro, EGF displayed no trophic activity-even at 30 ng/ml. Treatment of mesencephalic cultures with EGF (3 ng/ml) for 20 days stimulated [H-3]dopamine and [C-14]GABA uptake about 4-fold. While bFGF (3 ng/ml) also stimulated GABA uptake some 4-fold, dopamine uptake was increased almost 20-fold. Thus, EGF is also capable of enhancing the transmitter traits of selected central neuronal populations: however, the actions of bFGF appear to preferentially address dopaminergic cells.

Endothelin-1 and its receptors are widely distributed in the brain of rodents and humans. In view of its potent and long-lasting vasoconstrictor activity, a role of endothelin-1 has been proposed in brain ischemia. In the present paper, the local injection of endothelin-1 was utilized to induce ischemia in rat striatum. An evaluation of the rostrocaudal extension of the lesion is reported. By using intracerebral microdialysis, a marked increase of lactate and dopamine, but not glutamate, was observed in this region upon endothelin-1 administration. Moreover, preliminary data reported show a protective effect of ganglioside treatment on endothelin-1 lesion of rat striatum. The characteristics of the present model of brain ischemia are discussed in comparison with well characterized models, such as the Pulsinelli's four vessel occlusion and the middle cerebral artery occlusion.

The effect of aging on the binding parameters of 3H-SCH 23390, the most selective ligand of D-1 DA receptors, was studied in membrane preparations from the rat retina. DA-stimulated adenylate cyclase activity was also measured in order to better characterize the changes in retinal D-1 DA receptors induced by aging. The binding studies revealed that the density of 3H-SCH 23390 was increased (34 and 73%) in the retina of 14- and 26-month-old rats, when compared to young adult animals, respectively. In contrast, aging failed to alter the sensitivity of the adenylate cyclase to the action of DA. In fact, DA (10−6 M to 10−4 M) elicited a similar enhancement in cyclic AMP formation in retinal homogenates of both adult and senescent rats. Since dark adaptation increases the density of D-1 DA receptors in the retina of adult rats we studied the effect of light deprivation on 3H-SCH 23390 binding and DA-sensitive adenylate cyclase activity in the retina of senescent rats. As previously shown (25) light deprivation increased 3H-SCH 23390 binding and enhanced DA-sensitive adenylate cyclase activity in the retina of young adult rats. On the contrary, dark adaptation failed to increase 3H-SCH 23390 binding and to enhance DA-sensitive adenylate cyclase activity in the retina of senescent rats. Taken together these results indicate that D-1 DA receptors in the retina of aged rats have biochemical and functional properties different from those found in the retina of adult animals; these changes may result in an altered response to the physiological stimuli elicited by environmental lighting.

The effects of transient (30') forebrain ischemia (4 vessel occlusion model) on peptidergic neurons and astroglial cells in various diencephalic and telencephalic areas have been analyzed. The study was performed at various time intervals of reperfusion, i.e. 4 h, 1, 7 and 40 days. Neuropeptide Y (NPY), somatostatin (SRIF), cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP) and arginin-vasopressin (AVP) immunoreactive (IR) neuronal systems and glial fibrillary acidic protein (GFAP)-IR glial cells have been visualized by means of the indirect immunoperoxidase procedure using the avidin-biotin technique. The analysis was performed by means of computer assisted microdensitometry and manual cell counting. At the hippocampal level a huge reduction of neuropeptide (CCK, SRIF, VIP) IR cell bodies was observed, still present 40 days after reperfusion. On the contrary, in the frontoparietal cortex the number of the neuropeptide (CCK, SRIF, VIP, NPY) IR neurons showed a decrease at 4 h, 1 and 7 days after reperfusion followed by a complete recovery at 40 days. A rapid reduction followed by an almost complete recovery (7 days after reperfusion) was also observed at striatal level where SRIF- and NPY-IR neurons were detected. A marked decrease of NPY-IR terminals was observed in the paraventricular and periventricular hypothalamic nuclei and in the paraventricular thalamic nucleus. AVP-IR was markedly reduced in the magnocellular part of the paraventricular nucleus throughout the analyzed period (7 days after reperfusion). GFAP-IR was increased in the hippocampal formation and neostriatum while a not consistent increase was observed at neocortical level. These data point to a differential recovery of peptide-IR and to a different astroglial response in the various brain areas after transient forebrain ischemia. Region-specific factors rather than factors related to neuronal chemical coding seems to play a major role in determining the vulnerability of neuronal populations to transient ischemia.