A biocompatible gelatin sponge scaffold confers robust tissue remodeling after spinal cord injury in a non-human primate model.

We previously constructed a three-dimensional gelatin sponge (3D-GS) scaffold as a delivery vehicle for therapeutic cells and trophic factors in the treatment of spinal cord injury (SCI), and this study aimed to assess the biosafety and efficacy of the scaffold in a non-human primate SCI model. However, because it has only been tested in rodent and canine models, the biosafety and efficacy of the scaffold should ideally be assessed in a non-human primate SCI model before its use in the clinic. No adverse reactions were observed over 8 weeks following 3D-GS scaffold implantation into in a Macaca fascicularis with hemisected SCI.

Immunomodulatory Mechanism and Potential Therapies for Perinatal Hypoxic-Ischemic Brain Damage.

Hypoxia-ischemia (HI) is one of the most common causes of death and disability in neonates. Currently, the only available licensed treatment for perinatal HI is hypothermia. However, it alone is not sufficient to prevent the brain injuries and/or neurological dysfunction related to HI.

Microglia mediated neuroinflammation - signaling regulation and therapeutic considerations with special reference to some natural compounds.

Neuroinflammation plays a central role in multiple neurodegenerative diseases and neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemic injury etc. In this connection, microglia, the key players in the central nervous system, mediate the inflammatory response process. In brain injuries, activated microglia can clear the cellular debris and invading pathogens and release neurotrophic factors; however, prolonged microglia activation may cause neuronal death through excessive release of inflammatory mediators.

Heterogeneity of Microglia Phenotypes: Developmental, Functional and Some Therapeutic Considerations.

Background: Microglia play a pivotal role in maintaining homeostasis in complex brain environment. They first exist as amoeboid microglial cells (AMCs) in the developing brain, but with brain maturation, they transform into ramified microglial cells (RMCs). In pathological conditions, microglia are activated and have been classified into M1 and M2 phenotypes.

Animal Venom Peptides as a Treasure Trove for New Therapeutics Against Neurodegenerative Disorders.

Background: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemic stroke, impose enormous socio-economic burdens on both patients and health-care systems. However, drugs targeting these diseases remain unsatisfactory, and hence there is an urgent need for the development of novel and potent drug candidates.

Methods: Animal toxins exhibit rich diversity in both proteins and peptides, which play vital roles in biomedical drug development.

A Modular Assembly of Spinal Cord-Like Tissue Allows Targeted Tissue Repair in the Transected Spinal Cord.

Tissue engineering-based neural construction holds promise in providing organoids with defined differentiation and therapeutic potentials. Here, a bioengineered transplantable spinal cord-like tissue (SCLT) is assembled in vitro by simulating the white matter and gray matter composition of the spinal cord using neural stem cell-based tissue engineering technique. Whether the organoid would execute targeted repair in injured spinal cord is evaluated.

Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies.

Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection.

Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue.

We have reported previously that bone marrow mesenchymal stem cell (MSC)-derived neural network scaffold not only survived in the injury/graft site of spinal cord but also served as a "neuronal relay" that was capable of improving the limb motor function in a complete spinal cord injury (SCI) rat model. It remained to be explored whether such a strategy was effective for repairing the large spinal cord tissue loss as well as restoring motor function in larger animals. We have therefore extended in this study to construct a canine MSC-derived neural network tissue in vitro with the aim to evaluate its efficacy in treating adult beagle dog subjected to a complete transection of the spinal cord.

Hypoxia and myelination deficits in the developing brain.

Myelination is a complex and orderly process during brain development that is essential for normal motor, cognitive and sensory functions. Cellular and molecular interactions between myelin-forming oligodendrocytes and axons are required for normal myelination in the developing brain. Oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into mature myelin-forming oligodendrocytes.

Retinal microglia - A key player in healthy and diseased retina.

Microglia, the resident immune cells of the brain and retina, are constantly engaged in the surveillance of their surrounding neural tissue. During embryonic development they infiltrate the retinal tissues and participate in the phagocytosis of redundant neurons. The contribution of microglia in maintaining the purposeful and functional histo-architecture of the adult retina is indispensable.

Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment.

Glioma tumors constitute a significant portion of microglial cells, which are known to support tumor progression. The present study demonstrates that transforming growth factor-β (TGFβ) signaling pathway in microglia in a glioma environment is involved in tumor progression and pathogenesis. It has been shown that the TGFβ level is elevated in higher grades of gliomas and its signaling pathway regulates tumor progression through phosphorylation of SMAD2 and SMAD3, which form a complex with SMAD4 to regulate target gene transcription.

Neurotrophin-3 released from implant of tissue-engineered fibroin scaffolds inhibits inflammation, enhances nerve fiber regeneration, and improves motor function in canine spinal cord injury.

Spinal cord injury (SCI) normally results in cell death, scarring, cavitation, inhibitory molecules release, etc., which are regarded as a huge obstacle to reconnect the injured neuronal circuits because of the lack of effective stimulus. In this study, a functional gelatin sponge scaffold was used to inhibit local inflammation, enhance nerve fiber regeneration, and improve neural conduction in the canine.

Herbal Compounds with Special Reference to Gastrodin as Potential Therapeutic Agents for Microglia Mediated Neuroinflammation.

Background: Activated microglia play a pivotal role neurodegenerative diseases by producing a variety of proinflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin- 1beta (IL-1β) and nitric oxide (NO) that are toxic to neurons and oligodendrocytes.

Methods: In view of the above, suppression of microglia mediated neuroinflammation is deemed a therapeutic strategy for neurodegenerative diseases. Several potential Chinese herbal extracts have been reported to exert neuroprotective effects against neurodegenerative diseases targeting specifically at the activated microglia.

Perineurium-like sheath derived from long-term surviving mesenchymal stem cells confers nerve protection to the injured spinal cord.

The functional multipotency enables mesenchymal stem cells (MSCs) promising translational potentials in treating spinal cord injury (SCI). Yet the fate of MSCs grafted into the injured spinal cord has not been fully elucidated even in preclinical studies, rendering concerns of their safety and genuine efficacy. Here we used a rat spinal cord transection model to evaluate the cell fate of allograft bone marrow derived MSCs.

Production of proinflammatory mediators in activated microglia is synergistically regulated by Notch-1, glycogen synthase kinase (GSK-3β) and NF-κB/p65 signalling.

Microglia activation and associated inflammatory response are involved in the pathogenesis of different neurodegenerative diseases. We have reported that Notch-1 and NF-κB/p65 signalling pathways operate in synergy in regulating the production of proinflammatory mediators in activated microglia. In the latter, there is also evidence by others that glycogen synthase kinase 3β (GSK-3β) mediates the release of proinflammatory cytokines but the interrelationships between the three signalling pathways have not been fully clarified.

Biology of Microglia in the Developing Brain.

Microglia exist in different morphological forms in the developing brain. They show a small cell body with scanty cytoplasm with many branching processes in the grey matter of the developing brain. However, in the white matter such as the corpus callosum where the unmyelinated axons are loosely organized, they appear in an amoeboid form having a round cell body endowed with copious cytoplasm rich in organelles.

Tail Nerve Electrical Stimulation and Electro-Acupuncture Can Protect Spinal Motor Neurons and Alleviate Muscle Atrophy after Spinal Cord Transection in Rats.

Spinal cord injury (SCI) often results in death of spinal neurons and atrophy of muscles which they govern. Thus, following SCI, reorganizing the lumbar spinal sensorimotor pathways is crucial to alleviate muscle atrophy. Tail nerve electrical stimulation (TANES) has been shown to activate the central pattern generator (CPG) and improve the locomotion recovery of spinal contused rats.

The circumventricular organs.

The circumventricular organs (CVOs) are midline structures located around the third and fourth ventricles that are characterized by a lack of blood-brain barrier. The pineal gland, median eminence, neurohypophysis and the subcommisural organ are classified as secretory, whereas the subfornical organ, area postrema and the organum vasculosum of the lamina terminalis as the sensory CVOs. Glial cells consisting of astrocytes and microglia/macrophages are present in all these organs.

Scutellarin Attenuates Microglia-Mediated Neuroinflammation and Promotes Astrogliosis in Cerebral Ischemia - A Therapeutic Consideration.

Neuroinflammation plays an important role in different brain diseases including acute brain injuries such as cerebral ischemic stroke and chronic neurodegenerative diseases e.g. Alzheimer's disease etc.

Effects of electroacupuncture and the retinoid X receptor (RXR) signalling pathway on oligodendrocyte differentiation in the demyelinated spinal cord of rats.

Objectives: In spinal cord demyelination, some oligodendrocyte precursor cells (OPCs) remain in the demyelinated region but have a reduced capacity to differentiate into oligodendrocytes. This study investigated whether 'Governor Vessel' (GV) electroacupuncture (EA) would promote the differentiation of endogenous OPCs into oligodendrocytes by activating the retinoid X receptor γ (RXR-γ)-mediated signalling pathway.

Methods: Adult rats were microinjected with ethidium bromide (EB) into the T10 spinal cord to establish a model of spinal cord demyelination.

Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia.

Microglia activation and associated inflammatory response play pivotal roles in the pathogenesis of different neurodegenerative diseases including neonatal hypoxic brain injury. Here we show that caspase3 expression was upregulated in activated microglia after hypoxic exposure, and remarkably, the cell viability remained unaffected alluding to the possibility of a non-apoptotic role of caspase3 in activated microglia. Chemical inhibition of caspase3 suppressed microglia activation as evident by an obvious reduction in expression of proinflammatory mediators and NF-κB signaling activation.

Transitory cystic cavities in the developing mammalian brain - normal or anomalous?

Transitory cavities associated with the ventricular system represent probably one of the most unique features in the developing mammalian brain. In rodents, the cavities exist transiently in the developing brain and do not appear to be associated with any pathological events. Among the various cavities, the pyramidal-shaped cavum septum pellucidum (CSP) located beneath the corpus callosum and between the lateral ventricles is most well defined.

Transplantation of tissue engineering neural network and formation of neuronal relay into the transected rat spinal cord.

Severe spinal cord injury (SCI) causes loss of neural connectivity and permanent functional deficits. Re-establishment of new neuronal relay circuits after SCI is therefore of paramount importance. The present study tested our hypothesis if co-culture of neurotrophin-3 (NT-3) gene-modified Schwann cells (SCs, NT-3-SCs) and TrkC (NT-3 receptor) gene-modified neural stem cells (NSCs, TrkC-NSCs) in a gelatin sponge scaffold could construct a tissue engineering neural network for re-establishing an anatomical neuronal relay after rat spinal cord transection.

MicroRNAs: Key Players in Microglia and Astrocyte Mediated Inflammation in CNS Pathologies.

The significance of microglia and astrocytes in neural development, in maintaining synaptic connections and homeostasis in the healthy brain is well established. Microglia are dynamic immune cells of the brain that elicit an immune response during brain damage and also participate in tissue repair and regeneration, while astrocytes contribute to the local inflammatory response by producing proinflammatory cytokines and resolving neuronal damage through production of anti-inflammatory cytokines and neurotrophic factors. Recent efforts have focused on elucidating the epigenetic mechanisms which regulate glial cell behavior in normal and pathologic states.

Glutamate Inhibits the Pro-Survival Effects of Insulin-Like Growth Factor-1 on Retinal Ganglion Cells in Hypoxic Neonatal Rat Retina.

Glutamate that accumulates in injured brain tissue has been shown to hinder the neuroprotection rendered by insulin-like growth factor-1 (IGF-1). However, its role in attenuating the neuroprotective effect of IGF-1 in the hypoxic retina is unknown and the current study was aimed at elucidating this. One-day-old Wistar rats were exposed to hypoxia for 2 h and the retinas were studied at 3 h to 14 days after exposure.