Therapeutic and Prophylactic Effects of Amphotericin B Liposomes on Chronic Social Defeat Stress-Induced Behavioral Abnormalities in Mice.

Recently, innate immune system stimulants, such as lipopolysaccharide (LPS) and macrophage-colony stimulating factor (M-CSF), were reported to prevent and reverse chronic stress-induced behavioral abnormalities, suggesting that innate immune stimulation could be a potential strategy for the treatment and prevention of mental disorders. Amphotericin B liposome is a clinically available antifungal medication that can stimulate macrophages and microglia. We hypothesize that amphotericin B liposome may be used to prevent and reverse behavioral abnormalities triggered by chronic stress. As expected, our results showed that a single injection of amphotericin B liposome (1 mg/kg) immediately after stress cessation reversed the decrease in time spent in the interaction zone in the social interaction test (SIT) and the increase in immobility time in the tail suspension test (TST) and forced swimming test (FST) in mice caused by chronic social defeat stress (CSDS). In addition, a single injection of amphotericin B liposomes (1 mg/kg) 1 day before stress exposure was found to prevent the CSDS-induced decrease in time spent in the interaction zone in the SIT and the increase in immobility time in the TST and FST in mice. Pretreatment with minocycline to inhibit the innate immune response was able to abolish the reversal effect of post-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities and the prophylactic effect of pre-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities. These results demonstrate that amphotericin B liposomes have both therapeutic and prophylactic effects on chronic stress-induced behavioral abnormalities in mice by mobilizing the innate immune response.

Pharmacological Actions of Myricetin in the Nervous System: A Comprehensive Review of Preclinical Studies in Animals and Cell Models.

Myricetin is a natural flavonoid extracted from a variety of plants, such as medicinal herbs, vegetables, berries, and tea leaves. A growing body of evidence has reported that myricetin supplementation display therapeutic activities in a lot of nervous system disorders, such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, epilepsy, and glioblastoma. Myricetin supplementation can also protect against pathological changes and behavioral impairment induced by multiple sclerosis and chronic stress. On the basis of these pharmacological actions, myricetin could be developed as a potential drug for the prevention and/or treatment of nervous system disorders. Mechanistic studies have shown that inhibition of oxidative stress, cellular apoptosis, and neuroinflammatory response are common mechanisms for the neuroprotective actions of myricetin. Other mechanisms, including the activation of the nuclear factor E2-related factor 2 (Nrf2), extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (Akt), cyclic adenosine monophosphate-response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) signaling, inhibition of intracellular Ca2+ increase, inhibition of c-Jun N-terminal kinase (JNK)-p38 activation, and suppression of mutant protein aggregation, may also mediate the neuroprotective effects of myricetin. Furthermore, myricetin treatment has been shown to promote the activation of the inhibitory neurons in the hypothalamic paraventricular nucleus, which subsequently produces anti-epilepsy effects. In this review, we make a comprehensive understanding about the pharmacological effects of myricetin in the nervous system, aiming to push the development of myricetin as a novel drug for the treatment of nervous system disorders.

PLGA Nanoparticle Platform for Trans-Ocular Barrier to Enhance Drug Delivery: A Comparative Study Based on the Application of Oligosaccharides in the Outer Membrane of Carriers.

PURPOSE: The trans-ocular barrier is a key factor limiting the therapeutic efficacy of triamcinolone acetonide. We developed a poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) surface modified respectively with 2-hydroxypropyl-ß-cyclodextrin (2-HP-ß-CD), chitosan oligosaccharide and trehalose. Determination of the drug/nanoparticles interactions, characterization of the nanoparticles, in vivo ocular compatibility tests, comparisons of their corneal permeability and their pharmacokinetics in aqueous humor were carried out. METHODS: All PLGA NPs were prepared by the single emulsion and evaporation method and the drug-nanoparticle interaction was studied. The physiochemical features and in vitro corneal permeability of NPs were characterized while the aqueous humor pharmacokinetics was performed to evaluate in vivo corneal permeability of NPs. Ocular compatibility of NPs was investigated through Draize and histopathological test. RESULTS: The PLGA NPs with lactide/glycolide ratio of 50:50 and small particle size (molecular weight 10 kDa) achieved optimal drug release and corneal permeability. Surface modification with different oligosaccharides resulted in uniform particle sizes and similar drug-nanoparticle interactions, although 2-HP-ß-CD/PLGA NPs showed the highest entrapment efficiency. In vitro evaluation and aqueous humor pharmacokinetics further revealed that 2-HP-ß-CD/PLGA NPs had greater trans-ocular permeation and retention compared to chitosan oligosaccharide/PLGA and trehalose/PLGA NPs. No ocular irritation in vivo was detected after applying modified/unmodified PLGA NPs to rabbit's eyes. CONCLUSION: 2-HP-ß-CD/PLGA NPs are a promising nanoplatform for localized ocular drug delivery through topical administration.

Lycopene ameliorates PTSD-like behaviors in mice and rebalances the neuroinflammatory response and oxidative stress in the brain.

Posttraumatic stress disorder (PTSD) is a mental disorder that can translate into severe economic problems. Lycopene is an aliphatic hydrocarbon carotenoid extracted from plants, including papayas, tomatoes, and water melons. Previous studies have shown that lycopene can produce antidepressant-like effects in rodent models of depression. However, little is known about its anti-PTSD-like effect. This was addressed in the present study by using the single prolonged stress (SPS) protocol to induce PTSD-like behavioral deficits in mice. Our results showed that 12 days of lycopene treatment at the dose of 10 and 20 mg/kg, but not at 5 mg/kg, ameliorated the PTSD-like phenotype induced by SPS, including the increase in freezing time in contextual fear paradigm, the decrease in time and entries in open arms in elevated plus maze test, and the decrease in distance and time in the central area of the open field test, without affecting the mouse locomotor activity. Mechanistic studies revealed that lycopene treatment (20 mg/kg, 12 days) could suppress the SPS-induced increase in levels of interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-α (TNF-α), and nitrite in the hippocampus and prefrontal cortex in mice, as well as the increased markers that indicate high levels of oxido-nitrosative stress in the hippocampus and prefrontal cortex in SPS mice. Lycopene treatment (20 mg/kg, 12 days) also suppressed the SPS-induced decrease in brain derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex in mice. Overall, the anti-PTSD-like effect of lycopene may be associated with its anti-neuroinflammation and anti-oxidative stress activities.

Antidepressive properties of macrophage-colony stimulating factor in a mouse model of depression induced by chronic unpredictable stress.

Previous studies have reported that macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, can ameliorate chronic stress-induced depressive-like behaviors in mice. This indicates that M-CSF could be developed into a novel antidepressant. Here, we investigated the antidepressive properties of M-CSF, aiming to explore its potential values in depression treatment. Our results showed that a single M-CSF injection at the dose of 75 and 100 µg/kg, but not at 25 or 50 µg/kg, ameliorated chronic unpredictable stress (CUS)-induced depressive-like behaviors in mice at 5 h after the drug treatment. In a time-dependent experiment, a single M-CSF injection (100 µg/kg) was found to ameliorate the CUS-induced depressive-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug treatment. The antidepressant effect of the single M-CSF injection (100 µg/kg) in chronically-stressed mice persisted at least 10 days and disappeared at 14 days after the drug treatment. Moreover, 14 days after the first injection, a second M-CSF injection (100 µg/kg) still produced antidepressant effects at 5 h after the drug treatment in chronically-stressed mice who re-displayed depressive-like phenotypes. The antidepressant effect of M-CSF appeared to be mediated by the activation of the hippocampal microglia, as pre-inhibition of microglia by minocycline (40 mg/kg) or PLX3397 (290 mg/kg) pretreatment prevented the antidepressant effect of M-CSF in CUS mice. These results demonstrate that M-CSF produces rapid and sustained antidepressant effects via the activation of the microglia in the hippocampus in a dose- and time-dependent manner.

Apoptosis-triggered decline in hippocampal microglia mediates adolescent intermittent alcohol exposure-induced depression-like behaviors in mice.

Depression-alcohol addiction comorbidity is a common clinical phenomenon. Alcohol exposure in adolescence has been shown to induce depression-like behaviors in rodents. However, the mechanism of action for this type of depression remains unclear. Previous studies have reported that several different types of stress, such as chronic unpredictable stress and early social isolation, trigger depression-like symptoms in mice by inducing hippocampal microglial decline, which is mediated by the initial activation of the microglial cells. Since alcohol also activates microglia, we evaluated the dynamic changes in hippocampal microglia in mice receiving adolescent intermittent alcohol exposure (AIE). Our results showed that 14 days of AIE, followed by 21 days period of no treatment, induced behavioral abnormalities as well as a significant loss and dystrophy of hippocampal microglia in mice. We found that this AIE-induced decline in hippocampal microglia was mediated by both microglial activation and apoptosis, as (i) 1 day of alcohol exposure induced a distinct activation of hippocampal microglia followed by their apoptosis, and (ii) blocking the initial activation of hippocampal microglia by pretreatment with minocycline suppressed the AIE-induced apoptosis and loss of hippocampal microglia as well as the AIE-induced depression-like symptoms. Lipopolysaccharide (LPS), a classical activator of microglia, ameliorated the AIE-induced depression-like symptoms by reversing the decline in the hippocampal microglia. These results reveal a possible mechanism for AIE-induced depression and demonstrate that the restoration of hippocampal microglial homeostasis may be a therapeutic strategy for depression induced by alcohol intake and withdrawal.

Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress.

The decrease of microglia in the hippocampus is a novel mechanism for depression onset. Reversal of this decrease can ameliorate stress-induced depression-like behaviors in rodents. However, the property of this therapeutic strategy remains unclear. We addressed this issue by designing a series of behavioral experiments. Results showed that a single lipopolysaccharide (LPS) injection at the dose of 75 and 100 µg/kg, but not at 30 or 50 µg/kg, produced obvious antidepressant effects in chronic unpredictable stress (CUS) mice at 5 h after the drug administration. In the time-dependent experiment, a single LPS injection (100 µg/kg) ameliorated the CUS-induced depression-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug administration. The antidepressant effect of a single LPS injection persisted at least 10 days and disappeared at 14 days after the drug administration. 14 days after the first injection, a second LPS injection (100 µg/kg) still produced antidepressant effects in chronically-stressed mice who re-displayed depression-like behaviors at 5 h after the drug administration. The antidepressant effect of LPS appears to be dependent on microglia, as at 5 h after LPS administration (100 µg/kg), the CUS-induced decrease in microglial numbers and Iba-1 mRNA levels in the hippocampus was reversed markedly, and inhibition of microglia by minocycline (40 mg/kg) or PLX33297 (290 mg/kg) prevented the antidepressant effect of LPS in CUS mice. These results indicate that a single LPS injection displays rapid and sustained antidepressant effects in chronically stressed mice likely through stimulating hippocampal microglia.

A review for the neuroprotective effects of andrographolide in the central nervous system.

Andrographolide is compound extracted from Andrographis paniculata (A. paniculata), a traditional herb that has been used in ancient China and other parts of eastern Asia to treat an array of disorders, such as cancer, rheumatoid arthritis, diarrhea, upper respiratory tract infection, and laryngitis, for a very long history. The mechanisms of action of andrographolide in disease prevention and/or therapy include anti-inflammation, anti-oxidative stress, anti-apoptosis, and/or pro-apoptosis. Pharmacodynamic studies have shown that andrographolide can cross the blood brain barrier and distribute into different brain regions, and therefore its pharmacological effects in the central nervous system (CNS) have begun to be revealed in recent years. For example, andrographolide has been reported to reduce brain infarct volume in several models of cerebral ischemia. In models of Alzheimer's disease (AD), andrographolide not only reduces Aß aggregation, but suppresses neuroinflammatory response and synaptic dysfunction, which could be evidenced by the reversal of microglia-mediated production of pro-inflammatory cytokines as well as AD-associated decreases in synaptic proteins, such as postsynaptic membrane dense substance-95. Andrographolide may also inhibit the onset and/or progression of Parkinson's disease, multiple sclerosis, and surgery- or diabetes-induced cognitive impairment. Further, andrographolide has been shown to inhibit chronic stress-induced abnormalities in serum corticosterone levels, mood-associated behavior, and hippocampal neurogenesis, suggesting that andrographolide may have a potential to treat psychiatric disorders, such as anxiety and depression. In this review, we summarize and discuss the pharmacological effects of andrographolide in the CNS in hope of revealing more possibilities of andrographolide in disease prevention and/or therapy.