Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (

Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions

Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease. The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract. Berberine, an isoquinoline alkaloid, is known as its anti-inflammatory and therapeutic effects in experimental colitis. However, little research focused on its regulatory function on ENS. Therefore, we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro-immune interactions. Functional defects of enteric glial cells (EGCs), with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression, were observed in DSS-induced murine UC. Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC, closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation. , berberine showed direct protective effects on monoculture of EGCs, bone marrow-derived dendritic cells (BMDCs), T cells, and intestinal epithelial cells (IECs) in the simulated inflammatory conditions. Furthermore, berberine could modulate gut EGCs-IECs-immune cell interactions in the co-culture systems. In summary, our study indicated the EGCs-IECs-immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995-2015

Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators (rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995-2015 and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

Expression and Distribution of BDNF (Brain Derived Neurotrophic Factor) in the Rat Hypothalamus / 대한해부학회지

BDNF belongs to the neurotrophin family and important molecular mediator of functional and structural plasticity. The highest levels of BDNF are found in the hippocampus and hypothalamus of the adult rat. Hypothalamus is important because of its high degree of plasticity, but little is known about distribution of BDNF in hypothalamic nuclei. Therefore, it is necessary to study distribution and expression pattern of BDNF in each hypothalamic nuclei to understand changes of BDNF through various neural damages including spinal cord injury. Through this experiment, we found specific BDNF expression pattern in some regions of hypothalamus and the results are as follows. 1) BDNF expressions were found in median eminence, arcuate nucleus, supraoptic nucleus, and periventricular nucleus of rat hypothalamus. 2) BDNF immunoreactive cells and nerve fibers were of various shapes and sizes. 3) Glial cells also express BDNF in certain hypothalamic nuclei. These results seem to be useful for future investigations of neurochemical changes in the hypothalamus induced by various neural trauma or degenerative changes

Changes of BDNF (Brain Derived Neurotrophic Factor) Expression Associated with Urodynamic Changes in Rat Spinal Cord Injury Animal Model / 대한해부학회지

Spinal cord injury results in dramatic changes in the neurochemistry of peripheral and central micturition reflex pathways. We studied an animal model of spinal cord contusion injury using Sprague Dawley rats. Recoveries of motor and bladder functions were recorded, along with the changes in brain-derived neurotrophic factor (BDNF) in regions rostral and caudal to the injury site. Results are as follows: 1. Motor functions examined by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale were fully recovered 28 d after spinal cord injury. 2. Bladder functions, monitored urodynamically, changed from flaccid paralysis at 4 d after spinal cord injury to spastic paralysis at 14, 18, and 28 d. 3. BDNF immunoreactive neurons and glial cells were found in both gray and white matters of the normal spinal cord, and the numbers decreased gradually after spinal cord injury 4. BDNF enzyme linked immunosorbent assay (ELISA) results were almost the same as for immunohistochemistry, but the intensity of decrease was more prominent in the caudal than in the rostral regions. Distinguishing between the beneficial or detrimental effects of neurotrophic factors in the context of micturition reflexes or regenerative responses will be a challenge, but is essential to understanding the effects of therapies directed at blocking the effects of neuroactive compounds or neurotrophic factors.

Sciatic nerve regeneration using calcium phosphate coated conduit and brain-derived neurotrophic factor gene-transfected schwann cell in rat

PURPOSE OF STUDY: Peripheral nerve regeneration depends on neurotrophism of distal nerve stump, recovery potential of neuron, supporting cell like Schwann cell and neurotrophic factors such as BDNF. Peripheral nerve regeneration can be enhanced by the conduit which connects the both sides of transected nerve. The conduit maintains the effects of neurotrophism and BDNF produced by Schwann cells which can be made by gene therapy. In this study, we tried to enhance the peripheral nerve regeneration by using calcium phosphate coated porous conduit and BDNF-Adenovirus infected Schwann cells in sciatic nerve of rats. MATERIALS AND METHODS: Microporous filter which permits the tissue fluid essential for nerve regeneration and does not permit infiltration of fibroblasts, was made into 2mm diameter and 17mm length conduit. Then it was coated with calcium phosphate to improve the Schwann cell adhesion and survival. The coated filter was evaluated by SEM examination and MTT assay. For effective allogenic Schwann cell culture, dorsal root ganglia of 1-day old rat were extracted and treated with enzyme and antimitotic Ara-C. Human BDNF cDNA was obtained from cDNA library and amplified using PCR. BDNF gene was inserted into adenovirus shuttle vector pAACCMVpARS in which E1 was deleted. We infected the BDNF-Ad into 293 human mammary kidney cell-line and obtained the virus plaque 2 days later. RT-PCR was performed to evaluate the secretion of BDNF in infected Schwann cells. To determine the most optimal m.o.i of BDNF-Ad, we infected the Schwann cells with LacZ adenovirus in 1, 20, 50, 75, 100, 250 m.o.i for 2 hours and stained with beta-galactosidase. Rats(n=24) weighing around 300g were used. Total 14mm sciatic nerve defect was made and connected with calcium phosphate coated conduits. Schwann cells(1x10(6)) or BDNF-Ad infected Schwann cells(1x10(6)) were injected in conduit and only media(MEM) was injected in control group. Twelve weeks after surgery, degree of nerve regeneration was evaluated with gait analysis, electrophysiologic measurements and histomorphometric analysis. RESULTS: 1. Microporous Millipore filter was effective conduit which permitted the adhesion of Schwann cells and inhibited the adhesion of fibroblast. We could enhance the Schwann cell adhesion and survival by coating Millipore filter with calcium phosphate. 2. Schwann cell culture technique using repeated treatment of Ara-C and GDNF was established. The mean number of Schwann cells obtained 1 and 2 weeks after the culture were 1.54+/-4.0*10(6) and 9.66+/-9.6*10(6). 3. The mRNA of BDNF in BDNF-Ad infected Schwann cells was detected using RT-PCR. In Schwann cell 0.69 microgram/microliter of DNA was detected and in BDNF-Adenovirus transfected Schwann cell 0.795 microgram/microliter of DNA was detected. The most effective infection concentration was determined by LacZ Adenovirus and 75 m.o.i was found the most optimal. CONCLUSION: BDNF-Ad transfected Schwann cells successfully regenerated the 14mm nerve gap which was connected with calcium phosphate coated Millipore filter. The BDNF-Ad group showed better results compared with Schwann cells only group and control group in aspect to sciatic function index, electrophysiologic measurements and histomorphometric analysis.