Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease.

Astrocytes contribute to brain development and homeostasis and support diverse functions of neurons. These cells also respond to the pathological processes in Alzheimer's disease (AD). There is still considerable debate concerning the overall contribution of astrocytes to AD pathogenesis since both the protective and harmful effects of these cells on neuronal survival have been documented. This review focuses exclusively on the neurotoxic potential of astrocytes while acknowledging that these cells can contribute to neurodegeneration through other mechanisms, for example, by lowered neurotrophic support. We identify reactive oxygen and nitrogen species, tumor necrosis factor α (TNF-α), glutamate, and matrix metalloproteinase (MMP)-9 as molecules that can be directly toxic to neurons and are released by reactive astrocytes. There is also considerable evidence suggesting their involvement in AD pathogenesis. We further discuss the signaling molecules that trigger the neurotoxic response of astrocytes with a focus on human cells. We also highlight microglia, the immune cells of the brain, as critical regulators of astrocyte neurotoxicity. Nuclear imaging and magnetic resonance spectroscopy (MRS) could be used to confirm the contribution of astrocyte neurotoxicity to AD progression. The molecular mechanisms discussed in this review could be targeted in the development of novel therapies for AD.

Psychosis in a primary hyperparathyroidism patient with mild hypercalcemia: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

Implications of Systemic Inflammation and Periodontitis for Major Depression.

Increasing evidence suggests that infection and persistent low-grade inflammation in peripheral tissues are important pathogenic factors in major depression. Major depression is frequently comorbid with systemic inflammatory diseases/conditions such as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in which pro-inflammatory cytokines are overexpressed. A number of animal studies demonstrate that systemic inflammation induced by peripheral administration of lipopolysaccharide increases the expression of pro-inflammatory cytokines in both the periphery and brain and causes abnormal behavior similar to major depression. Systemic inflammation can cause an increase in CNS levels of pro-inflammatory cytokines associated with glial activation, namely, neuroinflammation, through several postulated pathways. Such neuroinflammation can in turn induce depressive moods and behavioral changes by affecting brain functions relevant to major depression, especially neurotransmitter metabolism. Although various clinical studies imply a causal relationship between periodontitis, which is one of the most common chronic inflammatory disorders in adults, and major depression, the notion that periodontitis is a risk factor for major depression is still unproven. Additional population-based cohort studies or prospective clinical studies on the relationship between periodontitis and major depression are needed to substantiate the causal link of periodontitis to major depression. If such a link is established, periodontitis may be a modifiable risk factor for major depression by simple preventive oral treatment.

Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report.

The authors present the case of a 24-year-old male with treatment-resistant schizophrenia, with predominant severe delusion and hallucination, who received bone marrow transplantation (BMT) for acute myeloid leukemia. After BMT, he showed a remarkable reduction in psychotic symptoms without administration of neuroleptics. He also showed drastic improvement in social functioning. Follow-up evaluations 2 and 4 years after BMT showed persistent significant improvement of the psychotic state and social functioning. Recent findings show that the major underlying pathogenic mechanism of schizophrenia is immune dysregulation. Thus, conceptually, BMT, a cellular therapy, that facilitates the counteractive processes of balancing inflammation by immune regulation, could produce beneficial clinical effects in patients with treatment-resistant schizophrenia. Further studies are required to define the true benefits of BMT for the possible curative treatment of schizophrenia.

Gold drug auranofin could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst.

Neuroinflammation contributes to the pathogenesis of neurological disorders. Anti-inflammatory treatments could potentially be used to slow down the progression of these diseases. We studied the anti-neuroinflammatory activity of gold compounds which have been used to treat rheumatoid arthritis. Non-toxic concentrations of auranofin (0.1-1 µM) significantly reduced the cytotoxic secretions by primary human microglia and microglia-like THP-1 promonocytic cells. Auranofin inhibited primed NADPH-oxidase dependent respiratory burst and secretion of tumor necrosis factor (TNF)-α and nitric oxide by monocytic cells. It had a direct neuroprotective effect on SH-SY5Y neuronal cells. Auranofin could have a novel application in the treatment of neurodegenerative diseases.

Purinergic responses of calcium-dependent signaling pathways in cultured adult human astrocytes.

BACKGROUND: The properties of Ca2+ signaling mediated by purinergic receptors are intrinsically linked with functional activity of astrocytes. At present little is known concerning Ca2+-dependent purinergic responses in adult human astrocytes. This work has examined effects of purinergic stimulation to alter levels of intracellular Ca2+ in adult human astrocytes. Ca2+-sensitive spectrofluorometry was carried out to determine mobilization of intracellular Ca2+ following adenosine triphosphate (ATP) or 3'-O-(4-benzoyl)benzoyl-ATP (Bz-ATP) stimulation of adult human astrocytes. In some experiments pharmacological modulation of Ca2+ pathways was applied to help elucidate mechanisms of Ca2+ signaling. RT-PCR was also performed to confirm human astrocyte expression of specific purinoceptors which were indicated from imaging studies. RESULTS: The endogenous P2 receptor agonist ATP (at 100 µM or 1 mM) applied in physiological saline solution (PSS) evoked a rapid increase of [Ca2+]i to a peak amplitude with the decay phase of response exhibiting two components. The two phases of decay consisted of an initial rapid component which was followed by a secondary slower component. In the presence of Ca2+-free solution, the secondary phase of decay was absent indicating this prolonged component was due to influx of Ca2+. This prolonged phase of decay was also attenuated with the store-operated channel (SOC) inhibitor gadolinium (at 2 µM) added to standard PSS, suggesting this component was mediated by SOC activation. These results are consistent with ATP activation of P2Y receptor (P2YR) in adult human astrocytes leading to respective rapid [Ca2+]i mobilization from intracellular stores followed by Ca2+ entry through SOC. An agonist for P2X7 receptor (P2X7R), BzATP induced a very different response compared with ATP whereby BzATP (at 300 µM) elicited a slowly rising increase in [Ca2+]i to a plateau level which was sustained in duration. The BzATP-induced increase in [Ca2+]i was not enhanced with lipopolysaccharide pre-treatment of cells as previously found for P2X7R mediated response in human microglia. RT-PCR analysis showed that adult human astrocytes in vitro constitutively express mRNA for P2Y1R, P2Y2R and P2X7R. CONCLUSION: These results suggest that activation of metabotropic P2YR (P2Y1R and/or P2Y2R) and ionotropic P2X7R could mediate purinergic responses in adult human astrocytes.

The histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates human astrocyte neurotoxicity induced by interferon-γ.

BACKGROUNDS: Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders. METHODS: We examined the effects of SAHA on interferon (IFN)-γ-induced neurotoxicity of human astrocytes and on IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 in human astrocytes. We also studied the effects of SAHA on the astrocytic production of two representative IFN-γ-inducible inflammatory molecules, namely IFN-γ-inducible T cell α chemoattractant (I-TAC) and intercellular adhesion molecule-1 (ICAM-1). RESULTS: SAHA significantly attenuated the toxicity of astrocytes activated by IFN-γ towards SH-SY5Y human neuronal cells. In the IFN-γ-activated astrocytes, SAHA reduced the STAT3 phosphorylation. SAHA also inhibited the IFN-γ-induced astrocytic production of I-TAC, but not ICAM-1. These results indicate that SAHA suppresses IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. CONCLUSION: Due to its anti-neurotoxic and anti-inflammatory properties, SAHA appears to have the therapeutic or preventive potential for a wide range of neuroinflammatory disorders associated with activated astrocytes.

Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers.

We examined the effects of L-type calcium channel blockers (CCBs) on toxicity exerted by activated human astrocytes and microglia towards SH-SY5Y human neuronal cells. The CCBs nimodipine (NDP) and verapamil (VPM) both significantly suppressed toxic secretions from human astrocytes and astrocytoma U-373 MG cells that were induced by interferon (IFN)-γ. NDP also inhibited neurotoxic secretions of human microglia and monocytic THP-1 cells that were induced by the combination of lipopolysaccharide and IFN-γ. In human astrocytes, both NDP and VPM reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3. They also inhibited the astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). These results suggest that CCBs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. L-type CCBs, especially NDP, might be a useful treatment option for a broad spectrum of neurodegenerative diseases, including Alzheimer disease, where the pathology is believed to be exacerbated by neurotoxic glial activation.

Pyrazole compound 2-MBAPA as a novel inhibitor of microglial activation and neurotoxicity in vitro and in vivo.

Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 2-MBAPA (R/S-(±)-2-Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer's disease (AD) brain. The compound at a non-toxic concentration inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compound inhibited microgliosis, but not astrogliosis, in amyloid-ß peptide (Aß)(1-42)-injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aß(1-42) injection. These results indicate that this novel pyrazole compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia.

Proton pump inhibitors reduce interferon-γ-induced neurotoxicity and STAT3 phosphorylation of human astrocytes.

Proton pump inhibitors (PPIs) are known to possess anti-inflammatory properties. Inflammatory processes, including astrocytic activation, are implicated in the pathogenesis of different neurodegenerative diseases. Our recent study has indicated that interferon (IFN)-γ-induced astrocytic neurotoxicity is mediated, at least in part, by phosphorylation of signal transducer and activator of transcription (STAT) 3. We therefore studied the effects of PPIs on IFN-γ-induced neurotoxicity and STAT3 activation of human astrocytes. Both lansoprazole (LPZ) and omeprazole (OPZ) significantly attenuated IFN-γ-induced neurotoxicity of human astrocytes and astrocytoma cells. These drugs inhibited IFN-γ-induced phosphorylation of STAT 3, but not STAT1. We found that LPZ significantly reduced secretion of IFN-γ-inducible T cell α chemoattractant from IFN-γ-activated astrocytes. Neither LPZ nor OPZ suppressed expression of intercellular adhesion molecule-1 by IFN-γ-activated astrocytes. These results suggest that PPIs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. PPIs that possess antineurotoxic properties may be a useful treatment option for Alzheimer's disease and other neuroinflammatory disorders associated with activated astrocytes.

STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes.

Activation of signal transducer and activator of transcription (STAT) 3 is observable in reactive astrocytes under certain neuropathological conditions. Interferon (IFN)-γ is shown to activate STAT3 in cultured rodent astrocytes. Here we investigated the effects of inhibiting STAT3 signaling on IFNγ-activated human astrocytes since we have recently demonstrated that human astrocytes become neurotoxic when stimulated by IFNγ. We found that 5'-deoxy-5'-(methylthio)adenosine (MTA) (300 µM), S3I-201 (10 µM), STAT3 inhibitor VII (3 µM) and JAK-inhibitor I (0.3 µM) had anti-neurotoxic effects on IFN-γ (50 U/ml)-activated astrocytes and U373-MG astrocytoma cells. Another inhibitor, AG490 (30 µM) had no significant effect. The active inhibitors also attenuated IFN-γ-induced phosphorylation of Tyr(705)-STAT3 and astrocytic expression of intercellular adhesion molecule-1 (ICAM-1). They also decreased astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). AG490, which did not affect the Tyr(705)-STAT3 phosphorylation or ICAM-1 expression, nevertheless reduced the I-TAC secretion. Because these results indicate that pharmacological inhibition of STAT3 signaling correlates with reduced astrocytic neurotoxicity and ICAM-1 expression, but not that of I-TAC secretion, we consider that STAT3 activation mediates, at least in part, the IFN-γ-induced neurotoxicity and ICAM-1 expression by human astrocytes.

Cultured adult porcine astrocytes and microglia express functional interferon-γ receptors and exhibit toxicity towards SH-SY5Y cells.

In vitro cultures of various glial cell types are common systems used to model neuroinflammatory processes associated with age-dependent human neurodegenerative diseases. Even though most researchers choose to use neonatal rodent brain tissues as the source of glial cells, there are significant variations in glial cell functions that are species and age dependent. It has been established that human and swine immune systems have a number of similarities, which suggests that cultured porcine microglia and astrocytes may be good surrogates for human glial cell types. Here we describe a method that could be used to prepare more than 90% pure microglia and astrocyte cultures derived from adult porcine tissues. We demonstrate that both microglia and astrocytes derived from adult porcine brains express functional interferon-γ receptors (IFN-γ-R) and CD14. They become toxic towards SH-SY5Y neuroblastoma cells when exposed to proinflammatory mediators. Upon such stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), adult porcine microglia, but not astrocytes, secrete tumor necrosis factor-α (TNF-α) while both cell types do not secrete detectable levels of nitric oxide (NO). Comparison of our experimental data with previously published studies indicates that adult porcine glial cultures have certain functional characteristics that make them similar to human glial cells. Therefore adult porcine glial cells may be a useful model system for studies of human diseases associated with adulthood and advanced age. Adult porcine tissues are relatively easy to obtain in most countries and could be used as a reliable and inexpensive source of cultured cells.

Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium.

Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca(2+). Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect.

Proton pump inhibitors exert anti-inflammatory effects and decrease human microglial and monocytic THP-1 cell neurotoxicity.

To explore whether proton pump inhibitors (PPIs) possess anti-inflammatory effects on microglia, we investigated the effect of lansoprazole (LPZ) and omeprazole (OPZ) on the toxic action towards SH-SY5Y neuroblastoma cells of supernatants from human microglia and THP-1 cells stimulated by lipopolysaccharide combined with interferon-gamma. In addition, we studied the effect of LPZ and OPZ on the THP-1 cell production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 using enzyme-linked immunosorbent assays. We found that both PPIs had a protective effect on the toxicity of supernatants and that there was a synergism of this effect with S-ibuprofen (IBP), a typical non-steroidal anti-inflammatory drug (NSAID). A similar protective effect of LPZ was observed with supernatants from stimulated human microglia. We also found that both PPIs significantly reduced the TNF-alpha secretion from stimulated THP-1 cells in a concentration dependent manner and that there was a trend towards such reduction of IL-6. These results indicate that PPIs possess anti-inflammatory effects and can decrease human microglial and monocytic neurotoxicity. They suggest that PPIs combined with NSAIDs may be effective in the treatment of a broad spectrum of neurodegenerative diseases associated with activated microglia.

Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells.

Astrocytes and microglia become activated in a broad spectrum of inflammatory neurodegenerative diseases. Activated microglia are widely believed to be the principal source of inflammation-induced neuronal degeneration in these disorders. To investigate the neurotoxic potential of human astrocytes, we exposed them and human astrocytic U-373 MG cells to a variety of inflammatory stimulants. We then assessed the effects of their supernatants on human SH-SY5 cells. When astrocytes and U-373 MG cells were stimulated with interferon (IFN)-gamma (150U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5mug/ml), tumor necrosis factor-alpha (10ng/ml) and interleukin-1beta (10ng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-gamma effect. The induced cytotoxicities were reversed by JAK inhibitor I, a potent and specific inhibitor of JAKs. This result indicates that the neurotoxic effect was proceeding through the IFN-gamma receptor (IFNGR)-JAK-STAT intracellular pathway. To establish that the IFNGR is expressed on both cultured astrocytes and U-373 MG cells, we performed RT-PCR on total RNA extracts to identify a specific IFNGR product. We showed the protein product on these cultured cells by immunocytochemistry using an antibody to IFNGR. Finally, using human postmortem material, we showed sharp upregulation of the IFNGR on activated astrocytes in affected areas in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-gamma and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.

Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro.

The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D(2) receptor partial agonist. Atypical antipsychotics, all of which have dopamine D(2) receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-gamma-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-gamma-induced microglial activation. Not quinpirole, dopamine D(2) full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha from IFN-gamma-activated microglia and suppressed the IFN-gamma-induced elevation of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in murine microglial cells. Increased [Ca(2+)](i) has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-gamma-induced microglial activation through the suppression of IFN-gamma-induced elevation of [Ca(2+)](i) in microglia. Our results demonstrated that not only antipsychotics which have dopamine D(2) receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions.

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP-1 cell neurotoxicity.

Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP-1 cells, are lethal to cultured human neuroblastoma SH-SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP-1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L-[(12)C(6)] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) were grown in medium with heavy L-[(13)C(6)] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc-Asn-Phe-Pro-aldehyde and Z-Pro-Pro-aldehyde-dimethyl acetal, for their potential to reduce toxicity of stimulated THP-1 cell and human microglia supernatants towards SH-SY5Y cells. We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases.

Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide.

Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-gamma (IFN-gamma)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells with 100 U/ml of IFN-gamma resulted in an eightfold increase in IL-6 and a tenfold increase in NO into the culture medium. Pretreatment with the selective serotonin reuptake inhibitor fluvoxamine, the relatively selective noradrenaline reuptake inhibitor reboxetine, or the non-selective monoaminergic reuptake inhibitor imipramine, significantly inhibited IL-6 and NO production in a dose-dependent manner. These inhibitions were reversed significantly by SQ 22536, a cyclic adenosine monophosphate (cAMP) inhibitor, and, except for reboxetine, by the protein kinase A (PKA) inhibitor Rp-adenosine3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-3',5'-cAMPS). Lithium chloride, which is believed to act by inhibiting the calcium-dependent release of noradrenaline, had a different spectrum of action on microglial 6-3 cells. It enhanced IFN-gamma-stimulated IL-6 production and inhibited NO production. The inhibitory effect of lithium chloride was not reversed by either SQ 22536 or Rp-3',5'-cAMPS. These results suggest that antidepressants have inhibitory effects on IFN-gamma-activated microglia and these effects are, at least partially, mediated by the cAMP-dependent PKA pathway. On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-gamma-induced microglial activation.

Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid beta and interferon-gamma-induced microglial activation.

There is increasing evidence that microglial activation is one of the major pathogenic factors for Alzheimer's disease (AD) and the inhibition of the inflammatory activation of the microglia thus appears to be neuroprotective and a potentially useful treatment for AD. Phospholipids such as phosphatidylserine (PS) and phosphatidylcholine (PC) have been reported to modulate the immune function of phagocytes. In addition, PS has been reported to be a nootropics that can be used as nonprescription memory or cognitive enhancers. We therefore evaluated the effects of liposomes, which comprise both PS and PC (PS/PC liposomes), on the microglial production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and superoxide (*O(2)-) induced by amyloid beta (Abeta) and interferon-gamma (IFN-gamma). Pretreatment of microglia with PS/PC liposomes considerably inhibited the TNF-alpha, NO and *O(2)- production induced by Abeta/IFN-gamma. These results suggest that PS/PC liposomes have both neuroprotective and antioxidative properties through the inhibition of microglial activation, thus supporting the nootropic and antidementia effect of PS.

Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.

Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-gamma and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by IFN-gamma-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.