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Microglial Activation in Immunologically Induced Fatigue
Abstract
The clinical symptoms of chronic fatigue syndrome (CFS) have been shown to include disorders in the neuroendocrine, autonomic, and immune systems. On the other hand, it has been demonstrated that cytokines produced in the brain play significant roles in neural-immune interactions through their various central actions, such as activation of the hypothalamo-pituitary axis. We have recently developed an animal for fatigue induced by intraperitoneal (i.p.) injection of synthetic double-stranded RNAs, polyriboinosinic: polyribocytidylic acid (poly I:C, 3 mg/kg), in rats, and shown a decrease in the daily amounts of spontaneous running wheel activity to about 60% of preinjection level for more than 1 week. Simultaneously, mRNA for Interleukin-1β (IL-1β) increased for 1 day following poly I:C injection in the same hypothalamic nuclei. It is thus possible that brain cytokines may play some roles in the central mechanisms of fatigue. In this review article, we showed a role of microglia, one of the major cytokine-producing cells in the central nervous system, in the onset of fatigue using immunologically induced fatigue model rats. Microglia were morphologically activated in the medial preoptic area (MPO) and periventricular hypothalamic nucleus (Pe) 24-48 hrs after the injection of poly I:C. Pretreatment with minocycline for the consecutive 3 days (40 mg/kg/day), the poly I:C-induced decrease in the running wheel activity recovered to the base line levels, and the activation of microglia was suppressed. Following poly I:C injection, the expression of IL-1β was markedly increased in microglia in the MPO and Pe, since the IL-1β-positive cells were double-labeled with an antibody for the microglia marker, Iba-1. Furthermore, the poly I:C-induced increase in the expression of IL-1β was also prevented by pretreatment with minocycline. These findings, taken together, suggest that the activation of microglia, which is accompanied by the enhanced expression of IL-1β, is involved in the onset of the immunologically induced fatigue.
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One of the reasons for the insufficient effectiveness of treatment of acute ischemic stroke may be secondary inflammation of the brain tissue, which, according to the results of modern studies, significantly worsens the consequences and outcome of the disease.
The CNS, which consists of the brain and spinal cord, is continuously monitored by resident microglia and blood-borne immune cells such as macrophages, dendritic cells and T cells to detect for damaging agents that would disrupt homeostasis and optimal functioning of these vital organs. Further, the CNS must balance between vigilantly detecting for potentially harmful factors and resolving any immunological responses that in themselves can create damage if left unabated. We discuss the physiological roles of the immune sentinels that patrol the CNS, the molecular markers that underlie their surveillance duties, and the consequences of interrupting their functions following injury and infection by viruses such as JC virus, human immunodeficiency virus, herpes simplex virus and West Nile virus.
Recently it has been shown that mRNA of Iba1 (ionized calcium binding adaptor molecule 1), which was a novel calcium binding protein cDNA-cloned by our group, is specifically expressed in microglia in cultures of rat brain cells [Imai et al. Biophys. Biochem. Res. Commun., 224 (1996) 855–862]. In the present study, immunocytochemical and immunohistochemical examinations demonstrated that Iba1 protein is expressed in microglia alone both in cultured brain cells and in the brain, respectively. In a mixed cell culture of embryonic rat brain, immunocytochemically positive for Iba1 protein were the microglia but it was not detectable in neurons, astroglia, or oligodendroglia. Immunohistochemical staining of adult rat brain sections showed Iba1 protein to be specifically localised in ramified microglia. In addition, immunohistochemical staining and immunoblot analysis of activated microglia in the facial nucleus after facial nerve axotomy shows that expression of Iba1 protein was upregulated and peaked at 7 days. These results indicated that localisation of Iba1 protein is restricted to microglia both in vitro and in vivo, and that Iba1 protein plays a role in regulating the function of microglia, especially in the activated microglia.
The daily sleep–wake cycle is perhaps the most dramatic overt manifestation of the circadian timing system, and this is especially true for the monophasic sleep–wake cycle of humans. Considerable recent progress has been made in elucidating the neurobiological mechanisms underlying sleep and arousal, and more generally, of circadian rhythmicity in behavioral and physiological systems. This paper broadly reviews these mechanisms from a functional neuroanatomical and neurochemical perspective, highlighting both historical and recent advances. In particular, I focus on the neural pathways underlying reciprocal interactions between the sleep-regulatory and circadian timing systems, and the functional implications of these interactions. While these two regulatory systems have often been considered in isolation, sleep–wake and circadian regulation are closely intertwined processes controlled by extensively integrated neurobiological mechanisms.
Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.
Polyinosinic:polycytidic acid (poly I:C) is a synthetic double stranded RNA, which mimics with viral genome and mediates immune activation response similar to double stranded RNA virus infection into the brain. Microglial cells are the immune competent cells of the central nervous system having Toll like receptors-3 on their surface. Upon establishing that poly I:C infusion into the brain causes microgliosis by creating a viral infection model, the present study was designed to evaluate the effects of microglial activation following poly I:C infusion on motor activity. We infused 100 microl of 1% solution of Poly I:C in TBE buffer directly into the lateral ventricle and TBE buffer as vehicle to controls. A significantly higher microglial cell count as compared to control on 2, 3 and 7 days post infusion was recorded. Motor activity and microglial cell count was assessed in both controls and poly I:C infused rats on 1, 2, 3, 7, 14, 21 and 28 days post infusion. A significant decrease in motor activity and motor coordination occurred with respect to control. The results clearly demonstrate that microglial activation has a direct relevance with decreased motor activity. Findings could also have their importance in understanding the role of microglial cells on behavioral aspects in viral diseases.
Interleukin (IL)-18 is an important regulator of innate and acquired immune responses. Here we show that both the IL-18 and IL-18 receptor (IL-18R), which are induced in spinal dorsal horn, are crucial for tactile allodynia after nerve injury. Nerve injury induced a striking increase in IL-18 and IL-18R expression in the dorsal horn, and IL-18 and IL-18R were upregulated in hyperactive microglia and astrocytes, respectively. The functional inhibition of IL-18 signaling pathways suppressed injury-induced tactile allodynia and decreased the phosphorylation of nuclear factor kappaB in spinal astrocytes and the induction of astroglial markers. Conversely, intrathecal injection of IL-18 induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Our results indicate that IL-18-mediated microglia/astrocyte interactions in the spinal cord have a substantial role in the generation of tactile allodynia. Thus, blocking IL-18 signaling in glial cells might provide a fruitful strategy for treating neuropathic pain.
Intracerebroventricular infusion of femtomolar quantities of interleukin-1 (IL-1) or stimulated release of endogenous IL-1 in the brain suppresses various cellular immune responses, decreasing natural killer cell (NK) activity, response to mitogen, and interleukin-2 production of splenic and blood lymphocytes (an effect hereafter called "brain IL-1-induced immunosuppression"). The present study examines mechanisms by which IL-1 produces this effect. First, because IL-1 in the brain activates the pituitary-adrenal axis by stimulating release of corticotropin-releasing factor (CRF), the role of CRF was investigated. To block CRF, affinity-purified antibody to CRF was infused into the lateral ventricle 30 min before introduction of IL-1. When this was done, suppression of cellular immune responses that normally follow IL-1 infusion was completely prevented. Infusion with an equal quantity of non-CRF IgG prior to IL-1 was without effect. Second, the role of sympathetic nervous activity was examined. To block neural transmission at sympathetic ganglia, chlorisondamine (3.0 mg/kg) was injected intraperitoneally 60 min before IL-1 infusion. When this was done, suppression of immune responses by IL-1 was partially blocked. These results indicate that IL-1 in the brain suppresses various cellular immune responses by activating both the pituitary-adrenal axis and the sympathetic nervous system, and that these systems are both activated through the influence of IL-1 on CRF.
Serotonin (5HT) transporters (SERTs) are responsible for clearance of synaptic and plasma 5HT and are molecular targets for multiple therapeutic and addictive compounds. Recently brain and peripheral SERT cDNAs have been cloned and characterized functionally in transfected cells. Antipeptide (S365) and anti-fusion protein (CT-2) antibodies, directed at epitopes poorly conserved among other Na+/Cl- cotransporters, have been prepared to facilitate the identification and characterization of SERT proteins in native and transfected cells. Immunoprecipitations and immunoblots of rat/human SERT-transfected HeLa cells reveal specific SERT-immunoreactive glycoproteins absent from extracts of vector-transfected cells and absent when incubations were conducted using peptide- or fusion protein-absorbed antibody. In SDS-PAGE of membranes prepared from rat midbrain and cortex, SERTs migrate as single 76 kDa polypeptides with a relative abundance consistent with the known distribution of 5HT neurons and axonal projections. SERT-immunoreactive proteins are also detectable in platelet and pulmonary membranes, sites of peripheral 5HT uptake, but not in liver. Our studies also indicate that brain and platelet SERTs are formed from identical polypeptides differing significantly in their extent of N-linked glycosylation. Immunocytochemistry performed on rat brain sections with CT-2 antibody revealed SERT expression associated with brainstem raphe nuclei in a pattern virtually identical to that obtained by labeling adjacent sections with 5HT antisera. SERT-immunoreactive fibers were found to be widely distributed throughout the rodent brain, with highest density in forebrain regions known to receive a dense serotonergic innervation. In a similar manner, CT-2 antibody also detects endogenous expression of human SERT proteins, providing an opportunity for future studies on the modulation of transporter protein expression in neurologic and psychiatric disorders.
The purpose of this study was to characterize the basic biology of fever to lipopolysaccharide (LPS) in unrestrained mice. Although LPS has been shown to induce fevers in many laboratory animals (e.g., rats, guinea pigs, rabbits), there is some question of whether LPS causes a fall or rise in body temperature (Tb) in mice. Tb was measured by biotelemetry in unrestrained mice maintained at an ambient temperature of 30 degrees C. Intraperitoneal injections of LPS at doses of 1.0, 2.5, and 3.0 mg/kg induced dose-independent prompt decreases of Tb for 5.7 h. After this postinjection reduction, Tb increased and reached a peak at approximately 24 h postinjection. The peak rises in Tb were dose dependent. Changes in Tb due to LPS were accompanied by suppression of locomotor activity. Indomethacin, at a dose that did not affect normal Tb, enhanced the temperature-lowering effect of LPS as well as inhibited the febrile rise of Tb after LPS. Indomethacin did not modify the reduction in activity caused by the injections of LPS. Food intake of the mice was decreased by LPS in a dose-dependent manner, and tolerance developed to a second injection of LPS. We conclude that freely moving mice can develop pronounced and reproducible fevers in response to LPS, which is different in time course, dose-dependent profile, induction of pyrogenic tolerance profile, and mode of inhibition by indomethacin from those responses that have been observed in other species studied so far.
To examine cognitive function in chronic fatigue syndrome.
Twenty patients with chronic fatigue syndrome recruited from primary care and 20 matched normal controls were given CANTAB computerised tests of visuospatial memory, attention, and executive function, and verbal tests of letter and category fluency and word association learning.
Patients with chronic fatigue syndrome were impaired, predominantly in the domain of memory but their pattern of performance was unlike that of patients with amnesic syndrome or dementia. They were normal on tests of spatial pattern recognition memory, simultaneous and delayed matching to sample, and pattern-location association learning. They were impaired on tests of spatial span, spatial working memory, and a selective reminding condition of the pattern-location association learning test. An executive test of planning was normal. In an attentional test, eight subjects with chronic fatigue syndrome were unable to learn a response set; the remainder exhibited no impairment in the executive set shifting phase of the test. Patients with chronic fatigue syndrome were also impaired on verbal tests of unrelated word association learning and letter fluency.
Patients with chronic fatigue syndrome have reduced attentional capacity resulting in impaired performance on effortful tasks requiring planned or self ordered generation of responses from memory.
We successfully isolated a rat cDNA clone encoding a novel EF hand protein with a molecular weight of about 17 kDa and designated this geneiba1(ionized calcium binding adapter molecule 1). The genomic copy of theiba1gene was located within a segment of the major histocompatibility complex class III region between theBat2andTNFαgenes. Theiba1gene was shown to be highly expressed in testis and spleen, but weakly expressed in brain, lung, and kidney. Among brain cells, theiba1gene was specifically expressed in microglia. A screening of hemopoietic cell lines showed that the Iba1 protein was clearly expressed in monoblastic cell lines but only very weakly expressed in myeloid cell lines. Iba1 protein is therefore suggested to act as an adapter molecule, mediating calcium signals that may function in a monocytic lineage including microglia.
Fatigue is a symptom associated with many disorders, is especially common in women and in older adults, and can have a huge negative influence on quality of life. Although most past research on fatigue uses human subjects instead of animal models, the use of appropriate animal models has recently begun to advance our understanding of the neurobiology of fatigue. In this review, results from animal models using immunological, developmental, or physical approaches to study fatigue are described and compared. Common across these animal models is that fatigue arises when a stimulus induces activation of microglia and/or increased cytokines and chemokines in the brain. Neurobiological studies implicate structures in the ascending arousal system, sleep executive control areas, and areas important in reward. In addition, the suprachiasmatic nucleus clearly plays an important role in homeostatic regulation of the neural network mediating fatigue. This nucleus responds to cytokines, shows decreased amplitude firing rate output in models of fatigue, and responds to exercise, one of our few treatments for fatigue. This is a young field but very important as the symptom of fatigue is common across many disorders and we do not have effective treatments.
A single type of high-affinity binding sites for IL-1 beta was identified in the rat hypothalamus (Kd=1.0 ± 0.2 nM) and cerebral cortex (Kd=1.3 ± 0.2 nM), but not in the pituitary. The maximum binding capacity (Bmax) in the hypothalamus (Bmax=75.4 ± 10.8 fmol/mg protein) was 4 times greater than in the cerebral cortex (Bmax=17.2 ± 1.5 fmol/mg protein). Neither various neuropeptides nor IL-2 appeared to influence the binding of [125I]IL-1 beta to the hypothalamic membrane preparations. The potency of unlabeled IL-1 alpha to replace the binding of [125I]IL-1 beta to the hypothalamic membrane preparations was considerably less than that of unlabeled IL-1 beta. These findings indicate that IL-1 beta receptors are heterogeneously distributed in the central nervous system and that IL-1 alpha does not bind with IL-1 beta receptors in the brain.
This study examined the effects of exercise on behavior and peripheral blood leukocyte apoptosis in a rat model of chronic fatigue syndrome (CFS). Thirty-six healthy male Sprague-Dawley rats were equally randomized into 3 groups: the control group, CFS model group and the exercise group in terms of body weight. A total of 25 rats entered the final statistical analysis due to 11 deaths during the study. CFS model was established by subjecting the rats in CFS model group and exercise group to electric shock, chronic restraint stress and cold water swim. Besides, rats in the exercise group took running wheel exercise. After a week of conditioning feeding, model construction and running wheel exercise were performed simultaneously, and lasted for 23 consecutive days. The behavior experiments, including running wheel exercise, open-field test, tail suspension test and Morris water maze test, were conducted, either before or after the model establishment. Rats were sacrificed and peripheral blood was obtained for the assessment of lymphocyte apoptosis index by flow cytometry (FCM). It was found that as compared with those in the control group, the weight of the rats was decreased obviously (P<0.01), the mobility time in the open-field and the tail suspension tests was shortened significantly (P<0.01), the time to locate the platform was enhanced (P<0.01) and the cell apoptosis index was increased substantially (P<0.01) in the CSF model group. Meanwhile, in comparison to the model group, the behavior in the open-field and the tail suspension tests was improved significantly (P<0.05), and the apoptosis index decreased remarkably (P<0.01) in the exercise group. It is concluded that sport intervention can prevent lymphocyte apoptosis and improve animal behavior rather than the memory.
Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions.
We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self-report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls.
Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores.
We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury-related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom.
Aging is frequently accompanied by a proinflammatory state with adverse health consequences. This state is commonly assessed by markers in serum, either in isolation or ad hoc combination. We sought, alternatively, to develop scores summarizing multiple markers in accordance with biology on inflammatory regulation and evaluate their value added for discriminating functional outcomes in older adults. Data came from InCHIANTI (Invecchiare in Chianti; Aging in the Chianti Area) study participants age 65 years and older. Serum concentrations of seven inflammatory biomediators were subjected to latent variable analysis implementing a biological model of counterbalancing up- and down-regulation processes. Resulting process constructs were approximated by principal component scores; these, and individual markers, were evaluated as predictors of mobility impairment and frailty status in regression analyses, adjusting for key confounders. The biomediators' interrelationships were well predicted by the hypothesized biology. The up-regulation score was independently associated with worsened mobility functioning and frailty risk. For mobility, the association was stronger than, persisted independently of, and accounted for association with each biomediator. The down regulation score was associated with frailty outcomes. We conclude that systemic inflammation is relevant to the process that leads to functional loss in older persons and can be validly measured through biologically informed summary of inflammatory markers.
Although 17beta-estradiol (E2) is reported to improve the inflammatory response after trauma-hemorrhage (T-H), it remains unknown whether E2 plays any role in the central nervous system after T-H. Microglial cells, resident central macrophages, are thought to play a central role in exacerbating cell-mediated inflammation. We hypothesized that T-H up-regulates microglial cell-mediated inflammatory response in the brain, and E2 produces central anti-inflammatory effects via negative regulation of microglial cells. Male Sprague-Dawley rats were subjected to sham operation (cannulation plus laparotomy) or T-H (midline laparotomy; mean blood pressure, 35 +/- 5 mmHg for 90 min followed by resuscitation) and immediately killed after resuscitation. Rats received vehicle or E2 (1 mg/kg body weight i.v.) at the onset of resuscitation. In other experiments, minocycline (40 mg/kg body weight i.p.), microglia inhibitor, was administered 1 h before T-H to prevent inflammatory response in the microglia after T-H. The plasma and hypothalamic tumor necrosis factor (TNF-alpha) levels were increased, along with the activation of microglial cells in T-H rats compared with shams. Furthermore, T-H increased microglial TNF-alpha productive capacity in vitro. 17beta administration after T-H prevented these inflammatory responses. In rats pretreated with minocycline, decreased microglial TNF-alpha production and hypothalamic TNF-alpha levels were observed, but plasma TNF-alpha levels were not altered after T-H. Thus, T-H induces inflammatory responses even in the hypothalamus, and E2 seems to be a useful adjunct for down-regulating microglial cell-mediated inflammatory response after T-H.
It is well established that mediators of peripheral inflammation are relayed to the brain and elicit sickness behavior via neuroinflammatory agents that target neuronal substrates. In the present study, we used double-stranded RNA (dsRNA), a viral replication intermediate, to mimic the acute phase of viral infection. C57BL/6 mice were injected intraperitoneally with 12 mg/kg of synthetic dsRNA, i.e., polyinosinic-polycytidylic acid (PIC). The treatment induced severe sickness behavior in the animals as revealed by the burrowing test performed 6 hr postinjection. PIC challenge also induced up-regulation of mRNA for several cytokines in the brain as determined by real-time quantitative RT-PCR. In all brain regions, i.e., the forebrain, brainstem, and cerebellum, the gene encoding the CXCL2 chemokine featured the most robust up-regulation over the basal level (saline-injected animals), followed by the genes encoding the CCL2 chemokine, interferon-beta (IFNbeta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and interleukin-1beta (IL-1beta). The forebrain featured the highest extent of up-regulation of the Ifnb gene, whereas the other genes attained the highest expression in the cerebellum. Most of the genes featured transient up-regulation, with peaks occurring 3-6 hr after PIC challenge. The TNFalpha, CCL2, CXCL2, IFNbeta, and IL-1beta messages remained profoundly up-regulated even at 24 hr. The expression of genes encoding inducible and neuronal nitric oxide synthase (NOS) in the brain was not affected by the peripheral PIC challenge. However, the endothelial NOS message was initially down-regulated and subsequently up-regulated, indicating stimulation of cerebral vasculature.
Chronic fatigue syndrome (CFS) is an idiopathic disorder in which the chief symptoms is profound fatigue. To explore the relationship between immune stimulation and fatigue, we developed a murine model for quantifying fatigue: reduction in voluntary running and delayed initiation of grooming after swimming. Inoculation of female BALB/c mice with Corynebacterium parvum antigen or the relatively avirulent Me49 strain of Toxoplasma gondii induced fatigue: baseline running reduced to less than 50 and 30% for 8 and 14 days, respectively, and delayed initiation of grooming after swimming in both immunologically stimulated groups. A threefold evaluation of serum transforming growth factor-beta levels, a cytokine increased in CFS patients, was found in fatigued C. parvum- and T. gondii-inoculated mice. This murine model appears promising for investigation of the pathogenesis of immunologically mediated fatigue.
The effects of rat interferon (IFN) on the electrically-induced potentiation of the synaptic transmission were studied in rat hippocampal slices by using extracellular field potential recordings. The treatment with rat IFN (120 U/ml) reduced the size of short-term potentiation (STP) and suppressed long-term potentiation (LTP). These IFN-induced effects were dose-dependent in the range of 50-500 U/ml. In addition, IFN slightly attenuated the potentiation when applied during the maintenance of LTP. Basal synaptic transmission was affected by IFN at concentrations greater than or equal to 250 U/ml. Following an acute exposure to IFN (500-200 U/ml), cultured embryonic neurones from rat hippocampus often exhibited an attenuation of N-methyl-D-aspartate-induced currents and a variation (increase or decrease) of voltage-activated Ca2+ current amplitude. A possible role of IFN as neuromodulator in mammalian brain during immune responses is discussed.
It has been proposed that oxygen-derived radicals, superoxide in particular, are involved in the alteration of blood-brain barrier permeability and the pathogenesis of brain edema following trauma, ischemia, and reperfusion injury. Using transgenic mice that overexpress the human gene for copper-zinc-superoxide dismutase, we studied the role of superoxide radicals in the blood-brain permeability changes, edema development, and delayed infarction resulting from cold-trauma brain injury. At 2 hours after a 30-second cold injury, cerebral water and Evans blue contents were reduced, respectively, from 80 +/- 0.2% and 132.7 +/- 12.9 micrograms/gm of dry weight for nontransgenic mice to 78.5 +/- 0.3% and 87.1 +/- 9.9 micrograms/gm of dry weight for transgenic mice. Infarction, as measured by 2,3,5-triphenyltetrazolium chloride staining, was reduced by 52% in transgenic brains. These data indicate that an increased level of superoxide dismutase activity in the brain reduces the development of vasogenic brain edema and infarction. Superoxide radicals play an important role in the pathogenesis of these lesions in cold-traumatized brain.
In conclusion, there is overwhelming evidence that within the CNS the primary sites of active HIV-1 infection are microglia. CNS infection may be related to the normal repopulation of the CNS by monocytes (microglial turnover) that carry latent infection into the CNS. Activation of viral infection may depend upon microglial differentiation, soluble factors (cytokines), and/or coexistent infections. Infection of microglia may disturb the normal hemostatic balance that exists between microglia and other glia, and between microglia and neurons, processes that are only recently being explored at the molecular level. The impact that HIV infection of microglia may have on synaptic integrity is unknown. Cytokines appear to be prime candidates as mediators of some of the adverse effects of microglial infection on other CNS cells, myelin and endothelial cells.
Plasma cortisol levels were significantly lower in a group of patients suffering from chronic fatigue (CF) than in a control group matched for age and sex. Social readjustment rating scores were significantly higher in the CF group, indicating their exposure to more severe and frequent stressful experiences. The incidence of rheumatic disorders was higher in the CF group and these conditions had developed after a period of CF, suggesting that CF and the associated diminished adrenocortical activity had played a part in their causation. Circadian variations in skin capillary resistance and circulating eosinophil cells in healthy subjects suffering from acute fatigue support the view that there is a mild adrenocortical insufficiency in fatigue.
The newer tetracyclines are defined as those tetracyclines available in the United States but not approved for veterinary use. These include demeclocycline, methacycline, doxycycline, and minocycline. Of these, doxycycline and minocycline appear to offer advantages that would render them useful in certain situations in veterinary medicine. Their major advantage lies in their greater lipid solubility relative to other tetracyclines. This characteristic probably accounts for their enhanced antimicrobial effectiveness for some organisms, more efficient absorption after oral administration, and enhanced distribution in the body. The principal excretory organ for doxycycline is the intestine, where the drug diffuses through the intestinal mucosa into the intestinal tract. This unique characteristic makes this drug useful in cases of preexisting renal dysfunction and may render this drug superior to other tetracyclines in the treatment of intestinal infections. Doxycycline is used in other countries for respiratory tract and intestinal tract diseases of poultry. The usefulness of doxycycline and minocycline in food-producing animals may be limited because of persistent drug residues. Minocycline has, in large doses, been used with streptomycin in the elimination of the carrier state of canine brucellosis. The superiority of doxycycline and minocycline, relative to other tetracyclines, in their distribution to areas of he body such as the eye, brain, cerebrospinal fluid, and prostate gland suggests that trials of their efficacy in tetracycline-sensitive infections of these areas are indicated. Pharmacokinetic studies designed to determine optimal dosage schedules have not been made for domestic animals. These determinations are necessary to evaluate most effectively the usefulness of the newer tetracyclines in veterinary medicine.
Cytokines exert diverse actions on the PNS and the CNS and have been implicated in neuronally mediated responses to disease and injury. Certain cytokines participate in the central control of host systemic responses to disease, acting as signals to and within the brain. These molecules are also involved in neuronal degeneration and repair in the PNS and CNS, and have been proposed as mediators of various neuropathologies. The actions, mechanisms of action and potential strategies for modifying cytokines in the nervous system will be considered in this review, which continues the discussion of cytokine expression and recognition published in the February issue of TINS.
The brain has been known to produce high levels of interferon-alpha (IFN-alpha) during viral infections. We investigated the central and peripheral mechanisms of the brain IFN-alpha-induced suppression of natural killer (NK) cytotoxicity in the rat. The activity of NK cells in the spleen and the peripheral blood decreased 30-120 min after intracerebroventricular (icv) injection of recombinant human IFN-alpha of > 1,000 U but not after its intraperitoneal injection. This effect was antagonized by pretreatment with icv naltrexone (NLTX). Splenic denervation was observed to completely abolish the IFN-alpha-induced suppression of NK activity, whereas bilateral adrenalectomy did not. Furthermore, this immunosuppression was blocked by an icv injection of an antagonist of corticotropin-releasing factor (CRF), alpha-helical CRF-(9-41). The icv injection of CRF resulted in reduced NK activity, which was not affected by NLTX. The results suggest that brain IFN-alpha activates the CRF system through central opioid receptors and thereby suppresses the NK cytotoxicity predominantly through splenic sympathetic innervation.
We studied whether muscle fatigue, metabolism, or activation are abnormal in the chronic fatigue syndrome (CFS). Subjects performed both an intermittent submaximal and a sustained maximal voluntary isometric exercise protocol of the tibialis anterior muscle. The extent of fatigue, metabolic response, and changes in both M-wave amplitude and twitch tension during exercise were similar in patients and controls. The response to systemic exercise was also normal in the patients. However, voluntary activation of the tibialis was significantly lower in the patients during maximal sustained exercise. The results indicate that patients with CFS have (1) normal fatigability and metabolism at both the intracellular and systemic levels, (2) normal muscle membrane function and excitation-contraction coupling, and (3) an inability to fully activate skeletal muscle during intense, sustained exercise. This failure of activation was well in excess of that found in controls, suggesting an important central component of muscle fatigue in CFS.
Proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha have been proposed to play a role in the pathogenesis of fatigue. In the present study we compared the susceptibility of two mouse strains to immunologically induced fatigue. Daily running of two strains of mice, Balb/c and C57BL/ 6, was assessed after a single injection of Corynebacterium parvum antigen (2 mg/mouse). Spontaneous running activity of each animal was compared to mean running distance prior to injection. To evaluate the involvement of cytokines in fatigue development, C57BL/6 mice were treated with antibodies to specific cytokines at the time of challenge with C. parvum antigen. Also, cytokine mRNA expression was analyzed in the brains of mice at different time periods after immunologic challenge. A significant difference in running activity between the two mice strains was observed after C. parvum antigen inoculation: C57BL/6 mice showing a greater (P < 0.05) reduction in running activity (relative to preinjection levels) and slower recovery to baseline than Balb/c mice. Injection of antibodies specific to either IL-1beta or TNF-alpha did not alter immunologically induced fatigue, suggesting a lack of involvement of these cytokines produced outside of the central nervous system (CNS). However, increased TNF-alpha and IL-1beta mRNA expression was found in the brains of C57BL/6 compared to that seen in Balb/c mice at 6, 10, and 15 days after C. parvum antigen injection. The elevated CNS cytokine mRNA expression corresponded to development of fatigue. These findings are consistent with the hypothesis that expression of proinflammatory cytokines within the CNS plays a role in the pathogenesis of immunologically mediated fatigue.
To investigate the role of the autonomic nervous system in the symptoms of patients with chronic fatigue syndrome (CFS) and delineate the pathogenesis of the orthostatic Intolerance and predisposition to neurally mediated syncope reported in this patient group.
Twenty-three CFS patients and controls performed a battery of autonomic function tests. The CFS patients completed questionnaires pertaining to autonomic and CFS symptoms, their level of physical activity, and premorbid and coexisting psychiatric disorders. The relationship between autonomic test results, cardiovascular deconditioning, and psychiatric disorders was examined with multivariate statistics and the evidence that autonomic changes seen in CFS might be secondary to a postviral, idiopathic autonomic neuropathy was explored.
The CFS subjects had a significant increase in baseline (P < 0.01) and maximum heart rate (HR) on standing and tilting (both P < 0.0001). Tests of parasympathetic nervous system function (the expiratory inspiratory ratio, P < 0.005; maximum minus minimum HR difference, P < 0.05), were significantly less in the CFS group as were measures of sympathetic nervous system function (systolic blood pressure decrease with tilting, P < 0.01; diastolic blood pressure decrease with tilting, P < 0.05; and the systolic blood pressure decrease during phase II of a Valsalva maneuver, P < 0.05). Twenty-five percent of CFS subjects had a positive tilt table test. The physical activity index was a significant predictor of autonomic test results (resting, sitting, standing, and tilted HR, P < 0.05 to P < 0.009); and the blood pressure decrease in phase II of the Valvalsa maneuver, P < 0.05) whereas premorbid and coexistent psychiatric conditions were not. The onset of autonomic symptoms occurred within 4 weeks of a viral infection in 46% of patients-a temporal pattern that is consistent with a postviral, idiopathic autonomic neuropathy.
Patients with CFS show alterations in measures of sympathetic and parasympathetic nervous system function. These results, which provide the physiological basis for the orthostatic intolerance and other symptoms of autonomic function in this patient group, may be explained by cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or both.
We assessed the role of glial cells in the uptake of serotonin (5-hydroxytryptamine, 5-HT). Primary cultures of rat and mouse cortical astrocytes took up and deaminated 5-HT. The antidepressants citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline inhibited this process. The presence of the mRNAs for the 5-HT transporter and monoamine oxidase-A (MOA-A) was established in cultured astrocytes and in adult rat brain areas with (midbrain and brainstem) and without (frontal cortex) serotonergic cell bodies after reverse transcription-polymerase chain reaction and hybridization with probes complementary to the cloned neuronal 5-HT transporter and MAO-A. To examine in vivo the role of astrocytes in the elimination of 5-HT from the extracellular brain space, 5-HT was perfused through dialysis probes implanted in the frontal cortex of conscious rats and its concentration was measured at the probe outlet. Tissue 5-HT recovery was dose-dependently inhibited by the concurrent perfusion of citalopram, fluoxetine and paroxetine, showing that it essentially measured uptake through the high-affinity 5-HT transporter. Rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT; 88% reduction of tissue 5-HT) displayed tissue 5-HT recovery slightly higher than sham-operated rats (55 +/- 2 vs. 46 +/- 3%, P < 0.001), a finding perhaps attributable to the astrogliosis induced by 5,7-DHT denervation. Rats lesioned with 6-hydroxydopamine showed tissue 5-HT uptake similar to controls, suggesting negligible reuptake of 5-HT by catecholaminergic terminals. These results are consistent with the presence of a glial component of 5-HT uptake in the rodent brain, sensitive to antidepressants, which takes place through a 5-HT transporter very similar or identical to that present in neurons.
Apoptosis has been known to contribute to neuronal death following a variety of brain insults. However, the role of vasogenic brain edema in neuronal apoptosis is unknown. We studied the temporal pattern of brain edema and neuronal apoptosis following cold injury. Cold injury-induced brain edema, which was detected by the increased water content in the injured hemisphere, reached its maximum level at 24 h and remained there at 72 h, whereas the blood-brain barrier breakdown detected by Evans Blue extravasation returned to the control value by 24 h after injury. Terminal deoxynucleotidyl transferase-mediated uridine-5'-triphosphate-biotin nick end labeling (TUNEL)-positive apoptotic cells were scattered in the center of the lesion at 1 h and were dispersed over the cold lesion at 24 h. The number of these TUNEL-positive cells was maximized in the periphery but decreased in the center at 72 h after cold injury. We postulate that secondary neuronal damage occurred not only through necrotic, but also apoptotic pathways, and that apoptotic neuronal death may result from vasogenic edema development and may contribute to the expansion of the lesion in both the acute and delayed phases after cold injury.
The major classes of glial cells, namely astrocytes, oligodendrocytes, and microglial cells were compared in parallel for their susceptibility to damage after combined hypoxia and hypoglycemia or hypoxia alone. The three glial cell types were isolated from neonatal rat brains, separated, and incubated in N2/CO2-gassed buffer-containing glucose or glucose substitutes, 2-deoxyglucose or mannitol (both nonmetabolizable sugars). The damage to the cells after 6 hours' exposure was determined at 0, 1, 3, 7 days based on release of lactate dehydrogenase and counting of ethidium bromide-stained dead cells, double-stained with cell-type specific markers. When 2-deoxyglucose replaced glucose during 6 hours of hypoxia, both oligodendrocytes and microglia rarely survived (18% and 12%, respectively). Astroglia initially increased the release of lactate dehydrogenase but maintained 98% to 99% viability. When mannitol, a radical scavenger and osmolarity stabilizer, replaced glucose during 6 hours of hypoxia, oligodendrocytes rarely survived (10%), astroglia survival remained at 99%, but microglia survival increased to 50%. After exposure to 6 and 42 hours, respectively, of hypoxic conditions alone, oligodendrocytes exhibited 10% survival whereas microglia and astroglia were only temporarily stressed and subsequently survived. In conclusion, oligodendrocytes, then microglia, are the most vulnerable glial cell types in response to hypoxia or hypoglycemia conditions, whereas astrocytes from the same preparations recover.
Chronic fatigue syndrome, which can occur after acute infection and last for years, is characterized by severe and persistent fatigue. Others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue. Voluntary running is a highly motivated activity in mice, which will often run 5-7 mi/day in our laboratory. Following 2 weeks of acclimation to running wheels with food and water available ad lib, female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behavior were determined. Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behavior. After the first several days of reduced running behavior, levels of running and grooming slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery. The pattern of running during recovery was intriguing in that BA mice first ran at normal levels just after the lights went out, but they stopped after only 1-2 h. As recovery proceeded, they gradually increased the duration of the running bout during the night. Because this model uses voluntary exertion and the ability to run for longer periods of time characterizes recovery, the model may be a good one for studying the biologic underpinnings of chronic fatigue.
Cultured astrocytes derived from neonatal rat brain exhibited high affinity, Na+-dependent, paroxetine and fluoxetine sensitive [3H]5-HT uptake. Reverse transcriptase-PCR demonstrated that astrocytes in culture expressed messenger RNA for the cloned serotonin transporter protein which has been characterised as the neuronal serotonin transporter. Although the serotonin transporter in cultured astrocytes displayed a Km value approximately 10 times greater than found in adult brain synaptosomes, these observations indicated that astrocytes in vitro may express the same serotonin transporter as neurons. Reverse transcriptase-PCR demonstrated the presence of serotonin transporter mRNA in the adult rat cerebral cortex, suggesting that astrocytes in vivo may express low levels of this mRNA. To investigate whether astrocytes in the adult CNS express functional serotonin transporters, glial plasmalemmal vesicles were prepared from cerebral cortex, representing a subcellular fraction composed primarily of vesicles derived from astrocytes. These vesicles were characterised by [3H]-glutamate and [3H]-dopamine uptake and by immunoblot analysis, using glial and synaptic markers: glutamate synthase, SNAP-25 and synaptobrevin. [3H]5-HT was taken up into glial plasmalemmal vesicles in a high affinity (Km approximately 40 nM), Na+ dependent, paroxetine-sensitive manner. The [3H]5-HT uptake capacity (Vmax) in these vesicles was approximately one quarter of that observed in synaptosomes. These data indicate that astrocytes in culture and in vivo are capable of 5-HT uptake via the previously characterised 'neuronal' serotonin transporter.
The frequent association of an active viral infection with the symptoms of CFS led researchers to hypothesize that chronic fatigue syndrome (CFS) is induced by a virus. Results of these studies indicated that despite clinical support for this hypothesis, there were no clear data linking viruses to CFS. In this overview, we will explore the interrelation of the immune, endocrine, and central nervous systems, and the possibility that stress and/or the reactivation/replication of a latent virus (such as Epstein Barr virus) could modulate the immune system to induce CFS. Relevant research conducted in the developing field of psychoneuroimmunology will be reviewed, with a particular focus on cytokine synthesis, natural killer (NK) cell activity, and T-lymphocyte function, as they relate to CFS.
Chronic fatigue syndrome (CFS) is associated with insidious and persistent immunologic abnormalities that have proved difficult to reproduce. The heterogeneity of CFS, the variable quality of immunologic assays and their performance, along with an almost complete absence of longitudinal studies of cellular immune abnormalities in CFS may explain this difficulty. However, in a significant proportion of cases, low levels of natural killer (NK) cell activity have been reported. This article will explore the mechanisms responsible for low NK cell activity, discuss the relation between levels of NK cell activity and health/disease, describe new findings on NK cell-brain interactions, and put forth a specific hypothesis for the role of NK cells in the pathogenesis of CFS.
The purpose of this study was to describe the sequence of psychosocial events and infections preceding the onset of chronic fatigue syndrome (CFS). This information was related to the temporal development of crucial symptoms in relation to the onset of, namely, fatigue, sadness, irritability, pain, and feeling of fever.
A personal interview was conducted in 46 patients (mean age, 39.5 years; SD, 9 years) who fulfilled international CFS criteria. These patients were matched with regard to age and gender to 46 carefully matched control subjects. Twenty-three percent of the study subjects were men, and 77% were women. The patient at first identified the month that coincided with the onset of CFS. Similarly, each control subject was asked to identify a "very difficult period" within approximately the same period as the patient with whom the control subject was matched. A list of 14 different life events was perused. Participants were asked to identify for each month whether each of the listed events had occurred. Furthermore, they were asked to rate the importance of the events they had experienced. In addition, for each of the cardinal symptoms (fatigue, sadness, irritability, pain, and feeling of fever) and for each month, the subjects were asked to rate, on a visual analogue scale, the symptom intensity. Also, the number of infections was noted.
A statistically significant group difference in fatigue intensity existed during the period 4 to 10 months before the onset of CFS. During the 3 months preceding the diagnosis for the CFS patients or the peak of the crisis for the control group, there was a dramatic rise in fatigue in both groups. The CFS group reached a much higher fatigue level, which leveled off somewhat during the first year of follow-up but still remained very high in comparison with the control group, which reached precrisis levels 4 months after the peak. Similar patterns were observed for fever and pain. With regard to sadness and irritability, no group difference was observed during the period preceding the crisis. In the patient group, the level stayed high throughout the whole first year of follow-up, whereas a slow return started in the control group; precrisis levels were reached after 1 year in this group. The prevalence ratio (CFS patients/control subjects) for negative events was around 1.0 for the periods 4 to 12 months preceding CFS but 1.9 during the quarter year preceding the onset. For infections, the prevalence ratio increased successively during the four quarters preceding CFS (from 1.4 to 2.3).
According to the retrospective self-reports, there were differences between the groups in fatigue, pain, and feeling of fever during the months preceding the crisis. With regard to depressive and irritable feelings, no preillness differences were reported between the groups. There was a reported excess prevalence of both infections and negative life events during the quarter year preceding the onset of CFS or crisis. Potential sources of error are discussed. These findings must be replicated in longitudinal studies.
Intracerebroventricular administration into sedentary mice of the high molecular mass fraction of cerebrospinal fluid (CSF) from exercise-exhausted rats produced a decrease in spontaneous motor activity [K. Inoue, H. Yamazaki, Y. Manabe, C. Fukuda, T. Fushiki, Release of a substance that suppresses spontaneous motor activity in the brain by physical exercise, Physiol. Behav. 64 (1998) 185-190]. CSF from sedentary rats had no such effect. This suggests the presence of a substance regulating the urge for motion as a response to fatigue. A bioassay system using hydra, a freshwater coelenterate, showed an activity indistinguishable from transforming growth factor-beta (TGF-beta) in the CSF from exercise-fatigued rats, while not in that from sedentary rats. The increase in the concentration of active TGF-beta in the CSF from exercise-fatigued rat was also ascertained by another bioassay system using mink lung epithelial cells (Mv1Lu). Injection of TGF-beta into the brains of sedentary mice elicited a similar decrease in spontaneous motor activity in a dose-dependent manner. Increasing the exercise load on rats raised both the levels of active TGF-beta and the activity of depression on spontaneous motor activity of mice in the CSF of rats. Taken together, these results suggest that exercise increases active TGF-beta in the brain and it creates the feeling of fatigue and thus suppresses spontaneous motor activity.
Corticotropin-releasing factor (CRF) is a peptide that is released from the hypothalamus and in widespread areas of the brain following exposure to stressors. It is considered to be a mediator of many of the effects of stress, and its analgesic properties have been demonstrated in many studies. However, for primarily methodological reasons, the effects of CRF in the central nervous system have been neglected whereas the peripheral effects of CRF have been overemphasized. We present evidence that: (1) CRF can act at all levels of the neuraxis to produce analgesia; (2) the release of beta-endorphin does not explain the analgesia following intravenous or intracranial CRF administration; (3) inflammation must be present for local CRF to evoke analgesia and (4) the analgesic effects of CRF show specificity for prolonged pain. These findings suggest that CRF may have a significant role in chronic pain syndromes associated with hypothalamic-pituitary-adrenal axis abnormalities. Furthermore, CRF may represent a new class of analgesics that merits further study. Implications for the relationship between stress and pain are discussed.
There is evidence from recent studies that the brain endothelium (of capillaries and/or larger vessels) may serve as a specific target for serotonin [5-hydroxytryptamine (5-HT)]. This neurotransmitter is expected to be involved in the regulation of the blood-brain barrier (BBB) permeability and/or of the cerebral blood flow via receptor-mediated mechanisms. Effective control of these processes depends on a speedy uptake and metabolism of released 5-HT molecules. To realize this, a similar mechanism of 5-HT uptake as in brain may exist at the BBB. In this study, we have demonstrated using RT-PCR that 5-HT transporter mRNA is present in the brain endothelium and that a saturable transport system for 5-HT is functionally expressed in immortalized rat brain endothelial cells (RBE4 cells). These cells take up [3H]5-HT by an active saturable process with a Km value of 397 +/- 64 nmol/L and a transport capacity of 51.7 +/- 3.5 pmol x g(-1) x min(-1). The 5-HT uptake depends on Na+, as indicated by the replacement of NaCl by LiCl. The 5-HT uptake was sensitive to specific 5-HT transport inhibitors such as paroxetine, clomipramine, fluoxetine, and citalopram but not to inhibitors of the vesicular amine transporter such as reserpine or tetrabenazine. Our results demonstrate that cerebral endothelial cells are able to participate actively in the removal and metabolism of the released 5-HT, which supports the concept of direct serotoninergic regulation of the BBB function.
Glial cells regulate some neural functions which depend on the homeostatic maintenance of extracellular calcium within narrow physiological ranges. In this study, the presence of microglia-specific ionized calcium binding adaptor molecule 1 (Iba1) was examined in the mouse olfactory bulb. A heterogenous pattern of Iba1-positive cells expression was observed between the main and accessory olfactory bulbs (MOB and AOB, respectively). While Iba1 was almost uniformly expressed among the laminae of the MOB, its expression showed spatial variations from the anterior to the posterior regions of the AOB. Double immunofluorescence was used to confirm that Iba1 is not expressed in astrocytes which stained for glial fibrillary acidic protein. Since Iba1 may mediate calcium signals in microglia, the observations suggest a potential involvement of Iba1 and hence microglia in olfactory bulb function and/or homeostasis. Together with our previous observation, this provides further support of a bulbar neuron-glia system of potential physiological significance.
Iba1 is a novel calcium-binding protein and is specifically expressed in microglia in the brain. It has been suggested that Iba1 plays an important role in regulation of the function of microglia. In the present study we examined time-dependent Iba1 expression after transient middle cerebral artery occlusion and characterized microglial activation in various brain regions.
Rat middle cerebral artery occlusion was induced by the intraluminal filament technique. After 1.5 hours of transient ischemia, Iba1 expression was examined by immunohistochemical and immunoblot analyses. The microglial activation in association with ischemic severity was characterized by double immunostaining with other specific markers.
In the peri-ischemic area, heavily Iba1 immunoreactive cells rapidly appeared at 3.5 hours after reperfusion. Immunoreactivity was further increased and peaked at 7 days. In the ischemic core, round Iba1-positive cells, which may be blood-borne monocytes, appeared from 24 hours and reached a peak at 4 to 7 days. Double immunostaining revealed that activated microglia in the peri-ischemic area upregulated Iba1 expression but were negative for the macrophage marker ED1. ED1-positive cells were clearly restricted to the ischemic core.
These findings suggest the following: (1) Iba1 expression may be associated with microglial activation in ischemic brain, and Iba1 immunostaining can be useful to evaluate the pathophysiological roles of activated microglia in ischemic injury. (2) Expression of ED1 antigen is strictly restricted to severe ischemic damage, whereas activated microglia in the peri-ischemic area showed Iba1 upregulation without ED1. Therefore, microglia may exhibit difference of antigenicity in the severity of ischemic brain injury.
Microglia are resident monocyte-lineaged cells in the brain. Their characteristic feature is that they react to injury and
diseases of the brain and become morphologically and functionally activated. Although some trigger molecules which activate
microglia are predicted to be released from injured or affected cells, such molecules have not yet been identified. The main
role of activated microglia is believed to be in brain defense, as scavengers of dead cells, and as immune or immunoeffector
cells. Recent biochemical and neurobiological studies have further indicated that they significantly affect the pathological
state and/or regulate the regenerative state and remodeling of the brain by producing a variety of biologically active molecules
including cytotoxic and neuro-trophic molecules.
In a former study, we have shown that patients suffering from chronic fatigue syndrome (CFS) or chronic pain, when questioned about their premorbid lifestyle, reported a high level of "action-proneness" as compared to control groups. The aim of the present study was to control for the patients' possible idealisation of their previous attitude towards action.
A validated Dutch self-report questionnaire measuring "action-proneness" (the HAB) was completed by 62 randomly selected tertiary care CFS and fibromyalgia (FM) patients, as well as by their significant others (SOs).
HAB scores of the patients and those of the SOs were very similar and significantly higher than the norm values. Whether or not the SO showed sympathy for the patient's illness did not influence the results to a great extent. SOs with a negative attitude towards the illness even characterized the patients as more "action-prone."
These results provide further support for the hypothesis that a high level of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS and FM.
To investigate the detailed actions of transforming growth factor-beta (TGF-beta) in the brain, which increase accompanied with continuity of exercise, the authors performed electroencephalogram (EEG) spectral analysis for 2 h after intracranial injection of TGF-beta in rats and compared with the effects of swimming exercise. Relative power values (power percent) of the theta frequency band (4-7 Hz) increased and power percent of the alpha frequency band (7-13 Hz) decreased after intracranial injection of TGF-beta. The directions of these changes of EEG after intracranial injection of TGF-beta were consistent with those after exercise. The EEG pattern produced by leucine-enkephalin (Leu-enk), a typical brain peptide related to exercise, was completely different from that after exercise. The results suggested that the increase in TGF-beta concentration in the brain is, at least partly, relevant to the change of neuronal activity after exercise.