AIM: To investigate and compare the effects of spinal D-(-)-2-amino-7-phosphonoheptanoic acid (AP-7) and 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX),two glutamate receptor antagonists, on the responses of dor...AIM: To investigate and compare the effects of spinal D-(-)-2-amino-7-phosphonoheptanoic acid (AP-7) and 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX),two glutamate receptor antagonists, on the responses of dorsal horn neurons to colorectal distension (CRD) in adult rats exposed to neonatal colon irritation (CI).METHODS: Hypersensitive SD rats were generated by CI during postnatal days 8, 10 and 12. Experiments on adult rats were performed using extracellular single-unit recording. The effects of spinal application of AP-7 (0.001,0.01, 0.1, 1 mmoL) were tested on the CRD-evoked neuronal responses in 16 controls and 17 CI rats. The effects of CNQX (0.2, 2, 5, 10 μmoL) were also tested on the CRD-evoked responses of 17 controls and 18 CI neurons.RESULTS: (1) The average responses of lumbosacral neurons to all intensities of CRD in CI rats were significantly higher than those in control rats; (2) In control rats, AP-7 (0.01 mmoL) had no significant effect on the neuronal response to all intensities of CRD (20,40, 60, 80 mmHg); while AP-7 (0.1 mmoL) inhibited the neuronal response to 80-mmHg CRD. By contrast, in CI rats, AP-7 (0.01-1 mmoL) attenuated the CRD-evoked neuronal responses to all distention pressures in a dosedependent manner; (3) In control rats, CNQX (2 μmoL)had no significantly effect on the neuronal response to all intensities of CRD; however, CNQX (5 μmoL) significantly attenuated the responses to CRD in the 40-80 mmHg range. By contrast, CNQX (2-10 μmoL)significantly decreased the neuronal responses in CI rats to non-noxious and noxious CRD in a dose-dependent manner.CONCLUSION: Our results suggest that spinal N-methyl-D-aspartate (NMDA) and non-NMDA receptors may contribute to the processing of central sensitivity in a neonatal CI rat model, but they may play different roles in it.展开更多
Objective Using optical imaging in brainstem slices, we studied evoked responses in the mouse cochlear (CN) and vestibular (VN) nuclei. Methods The use of optical imaging allowed us to visualize the spatiotemporal pat...Objective Using optical imaging in brainstem slices, we studied evoked responses in the mouse cochlear (CN) and vestibular (VN) nuclei. Methods The use of optical imaging allowed us to visualize the spatiotemporal patterns of excitatory propagation in the CN and VN. Optical recordings can differentiate excitatory propagation in the ventral CN(VCN) from that in the dorsal CN(DCN). Furthermore, we assessed the relative distribution of NMDA and non-NMDA receptors in these regions using the glutamate antagonists APV (NMDA receptor antagonist) and CNQX (non-NMDA receptor antagonist) in mouse brainstem slices during postnatal days 1 to 3. Results The average sensitivity to APV was 99.1% in the VCN, 76.0% in the DCN and 64.9% in the VN. The average sensitivity to CNQX was 0.9% in the VCN, 24.0% in the DCN and 35.1% in the VN. These results indicate that the effect of APV dominated in the VCN, while both APV and CNQX were effective antagonists in the DCN and VN. In the VN, the distribution of APV-and CNQX-sensitive cells was almost completely uniform. However, in the DCN the distribution of APV-and CNQX-sensitive cells was highly complex. The area that was more sensitive to CNQX was located in the superficial layer of the DCN while the area with a higher sensitivity to APV was located progressively in the deep layer. Conclusion This optical recording data suggests that there is a differential distribution of NMDA and non-NMDA receptor mediated neurotransmission in the VCN, DCN and VN.展开更多
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 usin...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 1995–2015and 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.展开更多
文摘AIM: To investigate and compare the effects of spinal D-(-)-2-amino-7-phosphonoheptanoic acid (AP-7) and 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX),two glutamate receptor antagonists, on the responses of dorsal horn neurons to colorectal distension (CRD) in adult rats exposed to neonatal colon irritation (CI).METHODS: Hypersensitive SD rats were generated by CI during postnatal days 8, 10 and 12. Experiments on adult rats were performed using extracellular single-unit recording. The effects of spinal application of AP-7 (0.001,0.01, 0.1, 1 mmoL) were tested on the CRD-evoked neuronal responses in 16 controls and 17 CI rats. The effects of CNQX (0.2, 2, 5, 10 μmoL) were also tested on the CRD-evoked responses of 17 controls and 18 CI neurons.RESULTS: (1) The average responses of lumbosacral neurons to all intensities of CRD in CI rats were significantly higher than those in control rats; (2) In control rats, AP-7 (0.01 mmoL) had no significant effect on the neuronal response to all intensities of CRD (20,40, 60, 80 mmHg); while AP-7 (0.1 mmoL) inhibited the neuronal response to 80-mmHg CRD. By contrast, in CI rats, AP-7 (0.01-1 mmoL) attenuated the CRD-evoked neuronal responses to all distention pressures in a dosedependent manner; (3) In control rats, CNQX (2 μmoL)had no significantly effect on the neuronal response to all intensities of CRD; however, CNQX (5 μmoL) significantly attenuated the responses to CRD in the 40-80 mmHg range. By contrast, CNQX (2-10 μmoL)significantly decreased the neuronal responses in CI rats to non-noxious and noxious CRD in a dose-dependent manner.CONCLUSION: Our results suggest that spinal N-methyl-D-aspartate (NMDA) and non-NMDA receptors may contribute to the processing of central sensitivity in a neonatal CI rat model, but they may play different roles in it.
基金supported by a grant-in-aid for scientific research to M.A.(No. 12771000), to T.Y. (No. 10671622) and to T.D. (No. 11771023) from the Ministry of Education, Japansupported in part by grants from the National Natural Science Fund of China (No. 30871398, 30730040, 30571017)Hi-Tech Research and Development Program of China (863) (#2007AA 02Z150)
文摘Objective Using optical imaging in brainstem slices, we studied evoked responses in the mouse cochlear (CN) and vestibular (VN) nuclei. Methods The use of optical imaging allowed us to visualize the spatiotemporal patterns of excitatory propagation in the CN and VN. Optical recordings can differentiate excitatory propagation in the ventral CN(VCN) from that in the dorsal CN(DCN). Furthermore, we assessed the relative distribution of NMDA and non-NMDA receptors in these regions using the glutamate antagonists APV (NMDA receptor antagonist) and CNQX (non-NMDA receptor antagonist) in mouse brainstem slices during postnatal days 1 to 3. Results The average sensitivity to APV was 99.1% in the VCN, 76.0% in the DCN and 64.9% in the VN. The average sensitivity to CNQX was 0.9% in the VCN, 24.0% in the DCN and 35.1% in the VN. These results indicate that the effect of APV dominated in the VCN, while both APV and CNQX were effective antagonists in the DCN and VN. In the VN, the distribution of APV-and CNQX-sensitive cells was almost completely uniform. However, in the DCN the distribution of APV-and CNQX-sensitive cells was highly complex. The area that was more sensitive to CNQX was located in the superficial layer of the DCN while the area with a higher sensitivity to APV was located progressively in the deep layer. Conclusion This optical recording data suggests that there is a differential distribution of NMDA and non-NMDA receptor mediated neurotransmission in the VCN, DCN and VN.
文摘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 1995–2015and 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.
