Evaluation of the effects of two TRH analogues on cerebral ischaemia

Latham, A.; Lye, R. H.; Shrewsbury-Gee, J.; Slater, P.

doi:10.1016/0167-0115(85)90117-x

Cited by 18 publications

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“…Latham et al 19 reported that long-lived TRH analogues (RX77368 and CG3509), unlike TRH, prevented the loss of cortical somatosensory evoked potentials in rats subjected to MCA occlusion; therefore, long-acting TRH analogues may show protective action against cerebral ischemia. We have already reported that YM-14673 acts longer than TRH in facilitating central nervous system activity.…”

Section: Discussionmentioning

confidence: 99%

“…These observations indicate that TRH possesses facilitatory effects on motor function and learned behavior. Recently, Latham et al 19 reported that TRH analogues (RX77368 and CG3509) with long lives prevented the loss of cortical somatosensory evoked potentials in MCA-occluded rats. Therefore, long-acting TRH analogues may show protective action against cerebral ischemia.…”

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confidence: 99%

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Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Yamamoto¹,

Tamura²,

Kirino³

et al. 1989

Stroke

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We observed the effects of a new thyrotropin-releasing hormone derivative, YM-14673 (A"*-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on behavioral changes in rats for 3 weeks after focal cerebral ischemia. Under halothane anesthesia, the left middle cerebral artery was occluded via a transretro-orbital approach. YM-14673 was administered just after the operation and once a day for 3 weeks. Neurologic deficits, including hemiplegia and abnormal posture, and disturbance of passive avoidance learning were present in solvent-treated control rats for the entire 3 weeks. YM-14673 at 0.1 or 0.3 mg/kg i.p. or 1 mg/ kg p.o. significantly accelerated the recovery of neurologic deficits and ameliorated cognitive disturbance compared with the solvent-treated controls although the drug at 0. 1112 On the other hand, there are only a few reports concerning pathologic and functional changes during the chronic phase of focal cerebral ischemia.11 Therefore, we monitored behavioral changes for 16 weeks after occlusion of the middle cerebral artery (MCA) in rats to investigate functional changes during the chronic phase of this model. 1314 In previous studies we observed neurologic deficits for 4 weeks after MCA occlusion, and learning behavior in a passive avoidance task was disturbed for 8 weeks when the rats were trained 3 days after MCA occlusion. 1314Yasuhara and Naito 15 reported that thyrotropinreleasing hormone (TRH) decreased the threshold for evoked muscular discharge induced by electrical Received June 8, 1988; accepted August 24, 1988. stimulation of the brain reticular formation in rabbits. Yamazaki et al 16 -18 reported that shortening of the latency of a passive avoidance task in rodents subjected to anoxia and treated with cycloheximide or scopolamine was prolonged by administration of TRH. These observations indicate that TRH possesses facilitatory effects on motor function and learned behavior. Recently, Latham et al 19 reported that TRH analogues (RX77368 and CG3509) with long lives prevented the loss of cortical somatosensory evoked potentials in MCA-occluded rats. Therefore, long-acting TRH analogues may show protective action against cerebral ischemia.Since TRH is known to be rapidly metabolized in the body, 20 -21 we have searched for TRH analogues that are more potent and last longer than TRH. (Figure 1), was found to possess analeptic actions such as antagonizing the effects of pentobarbital-induced sleeping time in mice and ameliorating the effects of conscious disturbance in mice with concussions.22 YM-14673 is approximately 10-100 times more potent than TRH in the context of central nervous facilitatory activities. describe the effects of YM-14673 on behavioral changes, including neurologic deficits and disturbance of learned behavior, during 3 weeks following focal cerebral ischemia in rats. Materials and MethodsWe used 67 male Wistar rats, each weighing approximately 300 g, housed in group cages under 12-hour light:dark conditions and given free access to laboratory cho...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Yamamoto¹,

Tamura²,

Kirino³

et al. 1989

Stroke

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“…Interestingly, therapeutic effects of TRH have been demonstrated in rodent models of ischemia [119][120][121] . Moreover, a recent study has shown that the TRH peptide is present in adult hippocampal NSPCs 122 , suggesting that TRH may affect these cells in a paracrine or autocrine manner.…”

Section: Thyrotropin-releasing Hormonementioning

confidence: 99%

Efficient non-viral transfection of adult neural stem/progenitor cells, without affecting viability, proliferation or differentiation

2005

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Stroke is one of the leading causes of chronic disability and death in the Western world. Today, no treatment can repair the cellular loss associated with an ischemic lesion. However, the discovery and dynamic regulation of neural stem/progenitor cells in the adult mammalian brain has resulted in exciting possibilities for future therapeutic interventions. Endogenous or grafted neural stem/progenitor cells are activated following an ischemic insult. These cells undergo directed migration towards infarcted areas, and differentiate in response to the insult. Unfortunately, the results of this regenerative effort are limited compared to the amount of tissue loss. This could be due to low survival of the recruited cells, but could also be explained by insufficient activation or dysfunctional lineage selection. Whether the lineage selection of neural stem/progenitor cells is altered following a lesion in the brain, what signals that are responsible for their activation or whether these cells can participate in post-lesion regeneration, astrogliosis or neuroprotection have yet to become clear. A greater understanding of these processes is necessary for finding ways to improve the endogenous regenerative capacity. We found that reactive astrocytes, a prominent part of the post-ischemic environment, induced astroglial differentiation of adult neural stem/progenitor cells in vitro. Moreover, astrocytes derived from these cells were shown to participate in glial scar formation in vitro. After studying gene expression in the peri-infarct region following focal ischemia, the expression of several genes was induced. We chose to focus our attention on one of these genes and its product, thyrotropin-releasing hormone (TRH). Immunoreactivity for TRH was found in several areas in both lesioned and intact brain regions, including in microglia present in the areas surrounding the lesion. Furthermore, TRH receptors were expressed on cultured neural stem/progenitor cells and TRH potently induced the proliferation of these cells. TRH is an interesting target for stroke treatment, but it also has many central effects in the brain and systemic administration may prove problematic. An interesting protocol for local delivery of TRH would be by grafting stem/progenitor cells, genetically engineered to secrete the peptide. In order to create a foundation for neuroprotective gene therapy, we developed efficient methods for non-viral transfection of neural stem/progenitor cells. Since neural stem/progenitor cells migrate towards the ischemic area we wanted to investigate whether these cells secreted factors that could protect neurons against excitotoxicity, the main inducer of cell death following a stroke. Mass spectrometric analysis of factors secreted from cultured neural stem/progenitor cells led to the identification of a novel neuroprotective peptide, which we termed pentinin. This peptide potently reduced excitotoxicity in both mature and immature neurons in an ex vivo hippocampal slice model. The results presented in this the...

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“…However, the role of opiate antagonists in the treatment of cerebral ischaemia remains controversial (Faden, 1984b). Recently we reported that early administration of RX 77368 (pGlu-His-[3,3'di Me]Pro NH2), a stabilized analogue of TRH, improves the outcome following middle cerebral artery (MCA) occlusion in the rat (Latham, Lye, Shrewsbury-Gee & Slater, 1985). We have now studied the effects of naltrexone in this stroke model.…”

Section: Pmentioning

confidence: 99%

Proceedings of the Physiological Society, 18‐19 April 1986, Sheffield Meeting: Poster Communications

1986

The Journal of Physiology

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Organ baths perfused with preheated solutions tend to have substantial temperature loss along the flow axis unless flow rates are very high and/or bath volumes very small. As both of these conditions do not suit our requirements, a bath with integrated heating facilities was designed. Adequate heat transfer and distribution were achieved by (1) employment of a round frame, (2) using stainless steel for frame and perfusion tubing, (3) inserting two sets of heating wires and the perfusion tubing in a heat-conducting solder (Ghhwiler & Bauer, 1975) and (4) connecting the tissue bath with two heat-stabilizing chambers through four (1 mm2) inlet and outlet channels. The main chamber has a diameter of 24 mm -suitable for our culture explants on round cover-slips. The bottom of the chamber consists of a round glass glued to the metal frame. Temperature is controlled by a linear thermistor. The control circuit compares the actual temperature with the preset temperature and feeds current according to that difference to the heating wires (Chabala, Sheridan, Hodge, Power & Walsh, 1985). With a flow rate of 2 ml/min it takes 7 min to achieve a preset temperature of 35 + 015 C starting from room temperature (22 'C). The uniformity of the temperature distribution in the chamber is illustrated by Fig. 1 B (flow rate, 2 ml/min; bath volume, 0 7 ml; preset temperature, 34 0 'C.

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Evaluation of the effects of two TRH analogues on cerebral ischaemia

Cited by 18 publications

References 0 publications

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Efficient non-viral transfection of adult neural stem/progenitor cells, without affecting viability, proliferation or differentiation

Proceedings of the Physiological Society, 18‐19 April 1986, Sheffield Meeting: Poster Communications

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