Magnetic nanoparticles (MNPs) generate heat when a high-frequency magnetic field (HFMF) is applied to them. Induction heat is useful not only for hyperthermia treatment but also as a driving force for drug-release. beta-Cyclodextrin (CD) can act as drug container because of its inclusion properties. Drugs incorporated in the CD can thus be released through the use of induction heating, or hyperthermic effects, by applying a HFMF. In this study, we have synthesized folic acid (FA) and CD-functionalized superparamagnetic iron oxide nanoparticles, FA-CD-SPIONs, by chemically modifying SPIONs derived from iron(III) allylacetylacetonate. FA is well-known as a targeting ligand for breast cancer tumor and endows the SPIONs with cancer-targeting capability. Immobilization of FA and CD on spinel iron oxide nanoparticles was confirmed by Fourier transform IR (FTIR) and X-ray photoelectron spectroscopy (XPS). The FA-CD-SPIONs have a hydrodynamic diameter of 12.4 nm and prolonged stability in water. They are superparamagnetic with a magnetization of 51 emu g(-1) at 16 kOe. They generate heat when an alternating current (AC) magnetic field is applied to them and have a specific absorption rate (SAR) of 132 W g(-1) at 230 kHz and 100 Oe. Induction heating triggers drug release from the CD cavity on the particle - a behavior that is controlled by switching the HFMF on and off. The FA-CD-SPIONs are noncytotoxic for cells. Thus, FA-CD-SPIONs can serve as a novel device for performing drug delivery and hyperthermia simultaneously.

Exogenous microglia pass through the blood-brain barrier and migrate to ischemic hippocampal lesions when injected into the circulation. We investigated the effect of exogenous microglia on ischemic CA1 pyramidal neurons. Microglia were isolated from neonatal mixed brain cultures, labeled with the fluorescent dye PKH26, and injected into the subclavian artery of Mongolian gerbils subjected to ischemia reperfusion neuronal injury. PKH26-labeled microglia migrated to the ischemic hippocampal lesion, resulting in increased numbers of surviving neurons compared with control animals, even when injected 24 h after ischemia. Interferon-c stimulation of isolated microglia enhanced the neuroprotective effect. Administration of exogenous microglia resulted in normal performance in a passive avoidance-learning task. Additionally, administration of exogenous microglia increased the expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in the ischemic hippocampus, and thus might have induced neurotrophin-dependent protective activity in damaged neurons. Peripherally injected microglia exhibited a specific affinity for ischemic brain lesions, and protected against ischemic neuronal injury in vivo. It is possible that administration of exogenous microglia can be developed as a potential candidate therapy for central nervous system repair after transitory global ischemia.

Dementia is a frequent complication of Parkinson's disease (PD) and usually occurs late in the protracted course of the illness. We have already reported numerous MHC class II-positive microglia in the hippocampus in PD patients, and that this phenomenon may be responsible for functional changes in the neurons and the cognitive decline in PD patients. In this study, we have investigated the distribution of activated microglia and the immunohistochemical and the mRNA expression of several cytokines and neurotrophic factors of the hippocampus in PD and dementia with Lewy bodies (DLB). The brains from five cases of PD and five cases of DLB that were clinically and neuropathologically diagnosed, and those from four normal controls (NC) were evaluated by immunohistochemistry using anti-HLA-DP, -DQ, -DR (CR3/43), anti-alpha-synuclein, anti-brain-derived neurotrophic factor (BDNF), and anti-glial fibrillary acidic protein antibodies. In addition, the mRNA expressions of cytokines (IL-1alpha, IL-1beta, TNF-alpha, IL-6, TGF-beta) and neurotrophic factors (BDNF, GDNF, NGF, NT-3) of these brains were evaluated by the reverse transcription-PCR method. MHC class II-positive microglia were distributed diffusely in the hippocampus of PD and DLB brains. Although the cytoplasm of pyramidal and granular cells of the hippocampus in NC brains was strongly stained by anti-BDNF antibodies, it was only weakly stained in PD and DLB brains. The mRNA expression of IL-6 was significantly increased in the hippocampus of PD and DLB brains, and that of BDNF was significantly decreased in the hippocampus of DLB brains. The increased number of activated microglia and the production of neurotrophic cytokines such as IL-6, together with the decreased expression of the neurotrophic factors of neurons in the hippocampus of PD and DLB brains, may be related to functional cellular changes associated with dementia.

Astronauts experience osteoporosis‐like loss of bone mass because of microgravity conditions during space flight. To prevent bone loss, they need a riskless and antiresorptive drug. Melatonin is reported to suppress osteoclast function. However, no studies have examined the effects of melatonin on bone metabolism under microgravity conditions. We used goldfish scales as a bone model of coexisting osteoclasts and osteoblasts and demonstrated that mRNA expression level of acetylserotonin O‐methyltransferase, an enzyme essential for melatonin synthesis, decreased significantly under microgravity. During space flight, microgravity stimulated osteoclastic activity and significantly increased gene expression for osteoclast differentiation and activation. Melatonin treatment significantly stimulated Calcitonin (an osteoclast‐inhibiting hormone) mRNA expression and decreased the mRNA expression of receptor activator of nuclear factor κB ligand (a promoter of osteoclastogenesis), which coincided with suppressed gene expression levels for osteoclast functions. This is the first study to report the inhibitory effect of melatonin on osteoclastic activation by microgravity. We also observed a novel action pathway of melatonin on osteoclasts via an increase in CALCITONIN secretion. Melatonin could be the source of a potential novel drug to prevent bone loss during space flight.

We examined the expression and function of beta-adrenergic receptor (beta-AR) subtypes in both isolated primary rat microglia and a rat microglial cell line. RT-PCR analyses revealed that microglia expressed beta(1)- and beta(2)-ARs but not beta(3)-ARs, whereas rat primary peritoneal macrophages expressed only beta(2)-ARs. Stimulation of beta-ARs on microglia by norepinephrine (NE) resulted in an increase in the level of intracellular cAMP and the subsequent expression of interleukin-1beta mRNA. These effects were prevented by propranolol. Similar results were obtained with other selective beta(1)-AR agonists and antagonists. beta(2)-ARs on microglia were also functional. It is possible that noradrenergic innervations participate in the control of microglial functions via beta(1)-ARs on microglia in the brain, because NE has high affinity for beta(1)- and beta(3)-ARs but little or no affinity for beta(2)-ARs. It seems physiologically significant that microglia can be controlled by NE, which predominates over epinephrine in the brain, whereas macrophages in peripheral tissues can be controlled by epinephrine, which is at higher levels in peripheral tissues.