Hailong Song

Triptolide treatment reduces Alzheimer’s disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD

The complex pathogenesis of Alzheimer’s disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.

Linking blast physics to biological outcomes in mild traumatic brain injury: Narrative review and preliminary report of an open-field blast model.

HighlightsBlast exposures are associated with traumatic brain injury (TBI); during recent conflicts most of these have been classified as mild TBI (mTBI).The role and mechanisms of primary blast wave injury remain controversial. We review blast models of TBI including shock tubes and open‐field blast.Our analyses of behavioral and pathological findings show that low level blast exposures (peak pressure < 100 kPa) induced lower mortality rates, fewer motor disabilities, and absence of lung injuries as compared to high level blast (peak pressure > 200 kPa).We present preliminary findings obtained from a reproducible open‐field blast murine model of mTBI representing a primary low level blast injury. Within scalability limits, this model closely mimics low level battlefield blast exposures and offers opportunities to advance the understanding of blast physics, resulting neuropathology, and underlying mechanisms leading to chronic effects of mTBI. ABSTRACT Blast exposures are associated with traumatic brain injury (TBI) and blast‐induced TBIs are common injuries affecting military personnel. Department of Defense and Veterans Administration (DoD/VA) reports for TBI indicated that the vast majority (82.3%) has been mild TBI (mTBI)/concussion. mTBI and associated posttraumatic stress disorders (PTSD) have been called “the invisible injury” of the current conflicts in Iraq and Afghanistan. These injuries induce varying degrees of neuropathological alterations and, in some cases, chronic cognitive, behavioral and neurological disorders. Appropriate animal models of blast‐induced TBI will not only assist the understanding of physical characteristics of the blast, but also help to address the potential mechanisms. This report provides a brief overview of physical principles of blast, injury mechanisms related to blast exposure, current blast animal models, and the neurological behavioral and neuropathological findings related to blast injury in experimental settings. We describe relationships between blast peak pressures and the observed injuries. We also report preliminary use of a highly reproducible and intensity‐graded blast murine model carried out in open‐field with explosives, and describe physical and pathological findings in this experimental model. Our results indicate close relationships between blast intensities and neuropathology and behavioral deficits, particularly at low level blast intensities relevant to mTBI.

Therapeutic effects of fucoidan in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: Role of NADPH oxidase-1.

To explore the effect of fucoidan treatment on oxidative stress‐mediated dopaminergic neuronal damage and its potential mechanisms.

Effects of aged garlic extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells

Aged garlic extract (AGE) is widely used as a dietary supplement on account of its protective effects against oxidative stress and inflammation. But less is known about specific molecular targets of AGE and its bioactive components, including N-α-(1-deoxy-D-fructos-1-yl)-L-arginine (FruArg). Our recent study showed that both AGE and FruArg significantly attenuate lipopolysaccharide (LPS)-induced neuroinflammatory responses in BV-2 microglial cells. This study aims to unveil effects of AGE and FruArg on gene expression regulation in LPS stimulated BV-2 cells. Results showed that LPS treatment significantly altered mRNA levels from 2563 genes. AGE reversed 67% of the transcriptome alteration induced by LPS, whereas FruArg accounted for the protective effect by reversing expression levels of 55% of genes altered by LPS. Key pro-inflammatory canonical pathways induced by the LPS stimulation included toll-like receptor signaling, IL-6 signaling, and Nrf2-mediated oxidative stress pathway, along with elevated expression levels of genes, such as Il6, Cd14, Casp3, Nfkb1, Hmox1, and Tnf. These effects could be modulated by treatment with both AGE and FruArg. These findings suggests that AGE and FruArg are capable of alleviating oxidative stress and neuroinflammatory responses stimulated by LPS in BV-2 cells.

Development of a Method and Validation for the Quantitation of FruArg in Mice Plasma and Brain Tissue Using UPLC–MS/MS

Aged garlic extract (AGE) is a popular nutritional supplement and is believed to promote health benefits by exhibiting antioxidant and anti-inflammatory activities and hypolipidemic and antiplatelet effects. We have previously identified N-α-(1-deoxy-d-fructos-1-yl)-l-arginine (FruArg) as a major contributor to the bioactivity of AGE in BV-2 microglial cells whereby it exerted a significant ability to attenuate lipopolysaccharide-induced neuroinflammatory responses and to regulate the Nrf2-mediated antioxidant response. Here, we report on a sensitive ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) protocol that was validated for the quantitation of FruArg in mouse plasma and brain tissue samples. Solid-phase extraction was used to separate FruArg from proteins and phospholipids present in the biological fluids. Results indicated that FruArg was readily absorbed into the blood circulation of mice after intraperitoneal injections. FruArg was reliably detected in the subregions of the brain tissue postinjection, indicating that it penetrates the blood–brain barrier in subnanomolar concentrations that are sufficient for its biological activity.

Ultrastructural brain abnormalities and associated behavioral changes in mice after low-intensity blast exposure

HighlightsAnalyzed comprehensive physical data from an open‐field primary blast model in mice.Observed low intensity blast (LIB) induced nanoscale brain abnormalities in mice.The ultrastructural damages occurred in the absence of necrosis and astrogliosis.Reported associated neurobehavioral dysfunctions resulting from LIB exposure.Provide insights into the pathogenesis of primary blast injury. ABSTRACT Explosive blast‐induced mild traumatic brain injury (mTBI), a “signature wound” of recent military conflicts, commonly affects service members. While past blast injury studies have provided insights into TBI with moderate‐ to high‐intensity explosions, the impact of primary low‐intensity blast (LIB)‐mediated pathobiology on neurological deficits requires further investigation. Our prior considerations of blast physics predicted ultrastructural injuries at nanoscale levels. Here, we provide quantitative data using a primary LIB injury murine model exposed to open field detonation of 350 g of high‐energy explosive C4. We quantified ultrastructural and behavioral changes up to 30 days post blast injury (DPI). The use of an open‐field experimental blast generated a primary blast wave with a peak overpressure of 6.76 PSI (46.6 kPa) at a 3‐m distance from the center of the explosion, a positive phase duration of approximate 3.0 milliseconds (ms), a maximal impulse of 8.7 PSI × ms and a sharp rising time of 9 × 10−3 ms, with no apparent impact/acceleration in exposed animals. Neuropathologically, myelinated axonal damage was observed in blast‐exposed groups at 7 DPI. Using transmission electron microscopy, we observed and quantified myelin sheath defects and mitochondrial abnormalities at 7 and 30 DPI. Inverse correlations between blast intensities and neurobehavioral outcomes including motor activities, anxiety levels, nesting behavior, spatial learning and memory occurred. These observations uncover unique ultrastructural brain abnormalities and associated behavioral changes due to primary blast injury and provide key insights into its pathogenesis and potential treatment.

Does Concurrent Use of Some Botanicals Interfere with Treatment of Tuberculosis

Millions of individuals with active TB do not receive recommended treatments, and instead may use botanicals, or use botanicals concurrently with established treatments. Many botanicals protect against oxidative stress, but this can interfere with redox-dependent activation of isoniazid and other prodrugs used for prophylaxis and treatment of TB, as suggested by results of a recent clinical trial of the South African botanical Sutherlandia frutescens (L.) R. Br. (Sutherlandia). Here we provide a brief summary of Sutherlandia’s effects upon rodent microglia and neurons relevant to tuberculosis of the central nervous system (CNS-TB). We have observed that ethanolic extracts of Sutherlandia suppress production of reactive oxygen species (ROS) in rat primary cortical neurons stimulated by NMDA and also suppress LPS- and interferon γ (IFNγ)-induced ROS and nitric oxide (NO) production by microglial cells. Sutherlandia consumption mitigates microglial activation in the hippocampus and striatum of ischemic brains of mice. RNAseq analysis indicates that Sutherlandia suppresses gene expression of oxidative stress, inflammatory signaling and toll-like receptor pathways that can reduce the host’s immune response to infection and reactivation of latent Mycobacterium tuberculosis. As a precautionary measure, we recommend that individuals receiving isoniazid for pulmonary or cerebral TB, be advised not to concurrently use botanicals or dietary supplements having antioxidant activity.

Early Abrogation of Gelatinase Activity Extends the Time Window for tPA Thrombolysis after Embolic Focal Cerebral Ischemia in Mice

Abstract Acute ischemic stroke (AIS) is caused by clotting in the cerebral arteries, leading to brain oxygen deprivation and cerebral infarction. Recombinant human tissue plasminogen activator (tPA) is currently the only Food and Drug Administration-approved drug for ischemic stroke. However, tPA has to be administered within 4.5 h from the disease onset and delayed treatment of tPA can increase the risk of neurovascular impairment, including neuronal cell death, blood-brain barrier (BBB) disruption, and hemorrhagic transformation. A key contributing factor for tPA-induced neurovascular impairment is activation of matrix metalloproteinase-9 (MMP-9). We used a clinically-relevant mouse embolic model of focal-cerebral ischemia by insertion of a single embolus of blood clot to block the right middle cerebral artery. We showed that administration of the potent and highly selective gelatinase inhibitor SB-3CT extends the time window for administration of tPA, attenuating infarct volume, mitigating BBB disruption, and antagonizing the increase in cerebral hemorrhage induced by tPA treatment. We demonstrated that SB-3CT attenuates tPA-induced expression of vascular MMP-9, prevents gelatinase-mediated cleavage of extracellular laminin, rescues endothelial cells, and reduces caveolae-mediated transcytosis of endothelial cells. These results suggest that abrogation of MMP-9 activity mitigates the detrimental effects of tPA treatment, thus the combination treatment holds great promise for extending the therapeutic window for tPA thrombolysis, which opens the opportunity for clinical recourse to a greater number of patients.

Gelatinase-Mediated Impairment of Microvascular Beds in Cerebral Ischemia and Reperfusion Injury

Stroke is one of the leading causes of death, and acute ischemic stroke (AIS) is the most common form. Tissue plasminogen activator (tPA) is the only FDA-approved drug for recanalization in AIS with narrow therapeutic window. In this chapter, we will discuss the activation of gelatinases (MMP-2/9), one of the major mediators in cerebral ischemia and reperfusion injury (CIRI) with exogenous tPA in AIS. First, we briefly overview the structure of microvascular beds and the homeostasis of neurovascular unit associated with the extracellular matrix (ECM). Then we review the gelatinase-mediated degradation of ECM and the impairment of microvascular beds in AIS. Moreover, we discuss the self-perpetuating loop of gelatinase activation in CIRI with exogenous tPA. At last, we literature available approaches showing protective functions through blocking the vicious circle of gelatinase activation, which may hold great promise in combined treatment with tPA in AIS.

Nanometer ultrastructural brain damage following low intensity primary blast wave exposure

Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial. Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step. This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 kPa using a murine model. The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge. We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury. Overall, these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention, diagnosis and treatment of blast induced TBI, particularly mTBI/concussion related to current combat exposures.