Effect of memantine, an anti-Alzheimer's drug, on rodent microglial cells in vitro.

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human ß-Amyloid (1-42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1ß, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-ß and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human ß-Amyloid (1-42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of ß-Amyloid (1-42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

ProBDNF induces sustained elevation of intracellular Ca2+ possibly mediated by TRPM7 channels in rodent microglial cells.

Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+ ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75NTR ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca2+ ]i through binding to the p75NTR , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.

Changes in interleukin-1 beta induced by rTMS are significantly correlated with partial improvement of cognitive dysfunction in treatment-resistant depression: a pilot study.

The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that provides a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). It has recently been demonstrated that TRD is associated with increased inflammatory process. In the present study, we investigated whether a relationship exists between changes in cognitive function and those in inflammatory cytokines before and after rTMS treatment. Eleven patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and serum concentration of inflammatory cytokines (interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α) were measured at baseline and at the endpoint of rTMS treatment. rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that partial changes in cognitive function and changes in IL-1ß were significantly correlated. The partial improvement of cognitive dysfunction by rTMS in the present study might be attributable to the reduction of peripheral IL-1ß levels. The present results should be replicated for verification in future studies.

Improvement Of Frontal Lobe Dysfunction And White Matter Integrity By rTMS In Treatment-Resistant Depression.

AIM: The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method providing a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). In the present study, we investigated whether a relationship exists between improvements in frontal lobe dysfunction induced by rTMS and improvement of white matter integrity revealed by diffusion tensor imaging (DTI) in TRD patients receiving rTMS treatment. METHODS: A total of 12 patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study (August 2013-January 2019). Frontal lobe function and depressive symptoms were assessed at baseline and at the endpoint of rTMS treatment. Fractional anisotropy (FA), as a measure of white matter integrity obtained from DTI, was investigated using a region-of-interest (ROI) approach. RESULTS: rTMS treatment significantly improved depressive symptom scores and some subscales of frontal lobe dysfunction. Category scores in the Word Fluency Test and scores on part 3 of the Color Stroop Test were improved independently of the improvement of depressive symptoms. In the ROI analysis, none of the FA increases in any region were correlated with improvement of any frontal lobe function (n = 12). CONCLUSION: Although rTMS resulted in partial improvement of frontal lobe dysfunction as well as white matter integrity, we found no correlation between improved frontal lobe dysfunction and improved white matter integrity in TRD patients.

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia.

BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.

An association between belief in life after death and serum oxytocin in older people in rural Japan.

OBJECTIVE: Previous research suggests that spirituality/religiosity has benefits for both mental and physical health, measured using biological indices such as cortisol and IL-6. However, there have been few studies concerning the association of religious beliefs with oxytocin, a neuropeptide hormone secreted by the pituitary. Levels of peripheral oxytocin are thought to reflect the strength of bonding and stress regulation in social relationships. As such, the oxytocin system may underpin the biological mechanisms by which belief in life after death is associated with good mental and physical health. Here, we examine associations between oxytocin and belief in life after death. METHODS: We recruited 317 community-dwelling people, aged 65 or older, without cognitive or mental deficits, and living in rural Japan. We recorded demographics, belief in life after death, and logical memory using the Wechsler Memory Scale. Levels of serum oxytocin were obtained using an enzyme immunoassay method. RESULTS: Serum oxytocin levels were higher among women than men and were negatively associated with strength of belief in life after death. CONCLUSIONS: Our findings could be interpreted differently depending on whether the anxiogenic or anxiolytic function of the oxytocin system is considered. Greater endorsement of afterlife beliefs may reduce secure attachment. Alternatively, based on the literature suggesting that basal levels of oxytocin are lower in those with reduced relational distress or anxiety, afterlife beliefs may play a role in these reductions. Copyright © 2016 John Wiley & Sons, Ltd.

Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder.

The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.

A patient with Alzheimer's disease complicated by elderly-onset Cushing's syndrome who had undergone surgical treatment for adrenocorticotropic hormone-independent macronodular adrenal hyperplasia.

Cushing's syndrome (CS) is a rare disorder, especially in older people. Loss of brain volume and neurocognitive impairment of varying degrees has been demonstrated in patients with CS. However, there is a large difference between the median age of presentation of CS and that of Alzheimer's disease. We herein report a case of a patient with Alzheimer's disease complicated by elderly-onset CS who had undergone surgical treatment for adrenal hyperplasia. Surgical correction of hypercortisolism seems to have slowed the progression of brain volume loss and cognitive dysfunction and improved psychiatric symptoms such as visual hallucination, restlessness, and psychomotor excitement. These improvements have remarkably reduced the burden on the patient's caregivers. The present case suggests that subclinical CS may be present, particularly in rapidly progressive dementia, and that surgical treatment of CS for neuropsychiatric symptoms is useful.

Abnormal behaviours during pramipexole treatment for Cotard's syndrome: a case report.

Cotard's syndrome is a relatively rare condition that involves a delusion of negation in which an individual believes he or she has lost his or her soul, is dead, or is without functional body systems. This syndrome is observed in various neuropsychiatric disorders but most commonly in mood disorders. Pramipexole has often been used in the adjunctive treatment of both bipolar and unipolar depression, and it is known to cause rare but serious adverse effects such as compulsive behaviours in the treatment of Parkinson's disease. Here we report a case of Cotard's syndrome in treatment-resistant major depression associated with abnormal behaviours that might be caused by pramipexole. In the present case, the patient's abnormal behaviours gradually disappeared about 2 months after the discontinuation of pramipexole. The hypoperfusion in the bilateral parieto-occipital lobe found on single-photon emission computed tomography suggests the presence of Lewy body disease pathology. Nonetheless, the patient's abnormal behaviours disappeared after the discontinuation of pramipexole, indicating that they are mainly attributable to pramipexole treatment. However, the possible existence of Lewy body pathology could facilitate the emergence of abnormal behaviours after treatment with pramipexole. The patient's abnormal behaviours, such as eating other patients' food and taking her medicine before the scheduled time, might differ from typical compulsive behaviours induced by pramipexole (such as pathological gambling and hypersexuality), but they could be regarded as disinhibition. Therefore, we should follow up on the clinical course of this case carefully through neuroimaging investigation and neurocognitive assessment.

A hyperdense artery sign and middle cerebral artery dissection.

We describe a rare case of spontaneous middle cerebral artery (MCA) dissection that caused cerebral infarction and subarachnoid hemorrhage (SAH), which also presented with a hyperdense artery sign. A hyperdense artery sign of the MCA in acute cerebral infarction strongly indicates thromboembolic MCA occlusion, which is often treated with thrombolytic therapy. However, thrombolytic therapy for intracranial artery dissections has both risks and benefits, due to the association of artery dissections with SAH. Therefore, it is important to keep in mind that an MCA dissection can also cause cerebral infarction with a hyperdense artery sign, particularly in young patients presenting with headache.