Combining Neuroprotective Treatment of Embryonic Nigral Donor Tissue with Mild Hypothermia of the Graft Recipient

2005 ◽  
Vol 14 (5) ◽  
pp. 301-309 ◽  
Author(s):  
Jenny Karlsson ◽  
ÅSa Petersén ◽  
Gunilla Gidö ◽  
Tadeusz Wieloch ◽  
Patrik Brundin
Keyword(s):  
Graft Survival ◽  
Dopaminergic Neurons ◽  
Mild Hypothermia ◽  
Combined Treatment ◽  
Cell Number ◽  
Behavioral Recovery ◽  
Donor Tissue ◽  
Before And After ◽  
Neuroprotective Treatment ◽  
Graft Implantation

Around 80–95% of the immature dopaminergic neurons die when embryonic ventral mesencephalic tissue is transplanted. Cell death occurs both during the preparation of donor tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat mesencephalic tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 μM) and the caspase inhibitor Ac.YVAD.cmk (500 μM) and transplanted the tissue into hemiparkinsonian rats kept hypothermic (32–33°C) or normothermic (37°C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50–57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary mesencephalic implants and stem cell grafts.

Ras antagonist inhibits growth and chemosensitizes human epithelial ovarian cancer cells

2006 ◽  
Vol 16 (Suppl 1) ◽  
pp. 200-206
Author(s):  
M. E. Beiner ◽  
H. Niv ◽  
R. Haklai ◽  
G. Elad-Sfadia ◽  
Y. Kloog ◽  
...  
Keyword(s):  
Cell Growth ◽  
Combined Treatment ◽  
Cell Number ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Ovarian Carcinomas ◽  
Ras Inhibition ◽  
Before And After ◽  
Human Ovarian Carcinoma ◽  
Farnesyl Thiosalicylic Acid

The objective of this article was to determine whether human ovarian carcinoma cells (OVCAR-3) express significant amounts of Ras oncogene and active Ras–guanosine triphosphate (GTP) and, if so, whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) inhibits their growth and chemosensitizes them to cisplatin. We assayed Ras and Ras-GTP in OVCAR-3 cells before and after FTS treatment. The effect of FTS on OVCAR-3 cell growth was assessed in terms of cell number. Because the OVCAR-3 cell line was derived from a patient who was refractory to cisplatin, we examined whether FTS enables cisplatin to induce death of these cells. Significant amounts of Ras and active Ras-GTP were expressed by OVCAR-3 cells and were reduced by 40% by FTS. FTS inhibited OVCAR-3 cell growth in a dose-dependent manner. When combined with cisplatin, FTS reduced the number of OVCAR-3 cells by 80%, demonstrating synergism between FTS and cisplatin. FTS, at a concentration range that allows downregulation of Ras and Ras-GTP in OVCAR-3 cells, also chemosensitizes these cells and inhibits their growth. These results suggest that ovarian carcinomas might respond well to Ras inhibition, both alone and when combined with cisplatin. The combined treatment would allow the use of smaller doses of chemotherapy, resulting in decreased cytotoxicity.

Effectiveness of Combining Manual Therapy and Acupuncture on Temporomandibular Joint Dysfunction: A Retrospective Study

2007 ◽  
Vol 35 (02) ◽  
pp. 203-208 ◽  
Author(s):  
Byung-Cheul Shin ◽  
Chung-Hyo Ha ◽  
Yung-Sun Song ◽  
Myeong Soo Lee
Keyword(s):  
Retrospective Study ◽  
Temporomandibular Joint ◽  
Manual Therapy ◽  
Randomized Clinical Trials ◽  
Combined Treatment ◽  
Mouth Opening ◽  
Temporomandibular Joint Dysfunction ◽  
Future Studies ◽  
Before And After ◽  
Maximal Mouth Opening

This retrospective study investigated the effects of combining manual therapy and acupuncture on the pain and maximal mouth opening (MMO), which were associated with temporomandibular joint dysfunction (TMD). The 49 TMD patients (15 men, 34 women; mean age = 30.47 years, SD = 13.52 years) were treated with a combination of acupuncture and manual therapy two or three times a week at the hospital. The pain and maximal mouth opening were assessed before and after 1 and 4 weeks of treatment. The combination therapy produced significant changes in pain levels ( p < 0.001) and mouth opening ( p < 0.001). All pairwise non-parametric comparison showed a significant improvement in pain ( p < 0.05 for all pairs) and MMO ( p < 0.05 for all pairs). These findings suggest that combining manual therapy and acupuncture decreases the pain level and increases the MMO of TMD patients. However, future studies should further investigate the efficacy of combined treatment on TMD with more rigorous randomized clinical trials.

Fetal nondopaminergic neural implants in parkinsonian primates

1991 ◽  
Vol 74 (1) ◽  
pp. 97-104 ◽  
Author(s):  
Krzysztof S. Bankiewicz ◽  
Robert J. Plunkett ◽  
David M. Jacobowitz ◽  
Irwin J. Kopin ◽  
Edward H. Oldfield
Keyword(s):  
Dopaminergic Neurons ◽  
Neural Implants ◽  
Behavioral Recovery ◽  
Foramen Of Monro ◽  
Caudate Nuclei ◽  
Content Type ◽  
Primate Brain ◽  
Brain Implants ◽  
Microsurgical Approach ◽  
Fine Print

✓ Implantation of fetal dopamine-containing tissue into preformed cavities in the caudate nucleus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian monkeys leads to behavioral recovery. Recovery may be related to two sources of dopamine: the grafted cells and/or the sprouted fibers from host dopaminergic neurons. The authors undertook this study to determine whether behavioral recovery requires release of dopamine by the implanted tissue, and to establish if nondopaminergic fetal central nervous system implants can induce sprouting of dopamine fibers in the primate brain and cause behavioral recovery. Rhesus monkeys with MPTP-induced hemiparkinsonism or full parkinsonism and a stable neurological deficit were used for this study. Cavities were created in the caudate nuclei anterior to the foramen of Monro via an open microsurgical approach. Fetal cerebellum or spinal cord was implanted into the preformed cavities of three monkeys. Control parkinsonian monkeys showed no recovery. However, implant-induced improvement was stable for up to 6 months after implantation. Sprouted dopaminergic fibers oriented from the ventral striatum and nucleus accumbens were found in the area of the tissue implant in the animals that received fetal grafts but were not present in the control monkeys. It is concluded that brain implants do not need to contain dopamine to induce functional recovery in MPTP-induced parkinsonian primates. Implant-induced and trophic factor-mediated dopaminergic sprouting by the host brain plays a role in the behavioral recovery and may well be responsible for the clinical improvement seen in parkinsonian patients after brain implants.

scholarly journals Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

2005 ◽  
Vol 49 (3) ◽  
pp. 468-472 ◽  
Author(s):  
Luiz Augusto Casulari ◽  
Fábio Celotti ◽  
Luciana A. Naves ◽  
Lucília Domingues ◽  
Carla Papadia
Keyword(s):  
Dopaminergic Neurons ◽  
Hormone Replacement ◽  
Hormonal Contraceptive ◽  
Primary Hypothyroidism ◽  
Trh Test ◽  
Pituitary Mass ◽  
Thyroid Hormone Replacement ◽  
Before And After ◽  
High Doses

Long term use of high doses of estrogen and the presence of chronic hyperprolactinemia may, at least in the rat, provoke lesions in the tuberoinfundibular dopaminergic (TIDA) neurons responsible for the control of prolactin (Prl) secretion. This occurrence, which is not yet well documented in humans, may have taken place in a patient on chronic oral hormonal contraceptive (OC) treatment who was seen for primary hypothyroidism, hyperprolactinemia and a pituitary mass. After thyroid hormone replacement, OC withdrawn and bromocriptine treatment, this patient could not maintain normal Prl levels, unless continuously treated with a dopaminergic agonist even when MRI was indicative of a normal situation. Function of TIDA neurons was investigated by TRH test (200µg IV) performed before and after treatment with 25mg carbidopa plus 250mg L-dopa every 4 hours for one day. Basal TSH was normal (3.9µU/mL) whereas basal Prl was high (67.5 ng/mL); both TSH and Prl levels appropriately increased after TRH: peaks 31.8µU/mL and 157.8 ng/mL, respectively. After treatment with carbidopa/L-dopa, basal TSH (1.6µU/mL) and Prl (34ng/mL) decreased and the response to TRH was partially blocked (10.3µU/mL and 61ng/mL, respectively). In spite of a normal response, we discuss the possibility that the persistence of hyperprolactinemia is due to lesion of the TIDA neurons produced by the long term use of high doses of estrogens and by the presence of chronic hyperprolactinemia.

scholarly journals Intrastriatal Ventral Mesencephalic Xenografts of Porcine Tissue in Rats: Immune Responses and Functional Effects

2000 ◽  
Vol 9 (2) ◽  
pp. 261-272 ◽  
Author(s):  
Lena C. Larsson ◽  
Kimberly A. Czech ◽  
Patrik Brundin ◽  
Håkan Widner
Keyword(s):  
Immune Responses ◽  
Graft Survival ◽  
Functional Recovery ◽  
Dopaminergic Neurons ◽  
Immunosuppressive Treatment ◽  
Neural Tissue ◽  
Scar Tissue ◽  
Rat Striatum ◽  
Intracerebral Transplantation ◽  
Ventral Mesencephalic

Transplantation of neural tissue from other species has the potential to improve function in patients with neurodegenerative disorders. We investigated the functional effects of embryonic porcine dopaminergic neurons transplanted in a rat model of Parkinson's disease and the immune responses to the grafts in immunosuppressed and nonimmunosuppressed hosts. Twenty-three rats with unilateral 6-hydroxydopamine lesions received dissociated, 27-day-old embryonic porcine ventral mesencephalic tissue in the right striatum. Eighteen rats received cyclosporine (10 mg/kg, IP, daily) during the whole period of 14 weeks, in combination with prednisolone (20 mg/kg, IP, daily) the first 4 days. Five rats served as nonimmunosuppressed controls. All rats were tested for amphetamine-induced rotational behavior at 3-week intervals. Two immunosuppressed rats were excluded due to severe side effects of the treatment. Functional recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six animals remained functionally recovered at 14 weeks and contained an average of 5750 ± 1450 (SEM) dopaminergic neurons. Between 9 and 14 weeks, three immunosuppressed rats rejected their grafts, based on rotation scores and immunohistochemical demonstration of cell infiltrates. One additional immunosuppressed rat showed evidence of ongoing rejection at 14 weeks. The striata in animals with ongoing or recent rejection contained large numbers of CD4- and CD8-positive lymphocytes, NK cells, macrophages, and microglia cells, whereas scar tissue was found in rats with grafts rejected at earlier time points (n = 11). Embryonic porcine ventral mesencephalic tissue matures in the adult rat striatum, reinnervates the host brain, and restores behavioral defects. Immunosuppressive treatment was necessary for long-term graft survival and functional recovery, but did not sufficiently protect from rejection mechanisms. Porcine neural tissue is an interesting alternative to embryonic human tissue for intracerebral transplantation in neurodegenerative diseases. However, to achieve stable graft survival in discordant xenogeneic combinations, an appropriate immunosuppressive treatment or donor tissue modifications are needed.

scholarly journals Combination of mild hypothermia with neuroprotectants has greater neuroprotective effects during oxygen-glucose deprivation and reoxygenation-mediated neuronal injury

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Xiao-Ya Gao ◽  
Jian-Ou Huang ◽  
Ya-Fang Hu ◽  
Yong Gu ◽  
Shu-Zhen Zhu ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Mild Hypothermia ◽  
Neuronal Damage ◽  
Combined Treatment ◽  
Neuronal Injury ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Single Treatment ◽  
Neuroprotective Effects ◽  
Apoptosis Pathway

Abstract Co-treatment of neuroprotective reagents may improve the therapeutic efficacy of hypothermia in protecting neurons during ischemic stroke. This study aimed to find promising drugs that enhance the neuroprotective effect of mild hypothermia (MH). 26 candidate drugs were selected based on different targets. Primary cultured cortical neurons were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to induce neuronal damage, followed by either single treatment (a drug or MH) or a combination of a drug and MH. Results showed that, compared with single treatment, combination of MH with brain derived neurotrophic factor, glibenclamide, dizocilpine, human urinary kallidinogenase or neuroglobin displayed higher proportion of neuronal cell viability. The latter three drugs also caused less apoptosis rate in combined treatment. Furthermore, co-treatment of those three drugs and MH decreased the level of reactive oxygen species (ROS) and intracellular calcium accumulation, as well as stabilized mitochondrial membrane potential (MMP), indicating the combined neuroprotective effects are probably via inhibiting mitochondrial apoptosis pathway. Taken together, the study suggests that combined treatment with hypothermia and certain neuroprotective reagents provide a better protection against OGD/R-induced neuronal injury.

Insulin resistance of skeletal muscle produced by hepatic parasympathetic interruption

1996 ◽  
Vol 270 (5) ◽  
pp. E858-E863 ◽  
Author(s):  
H. Xie ◽  
W. W. Lautt
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Liver Disease ◽  
Portal Vein ◽  
Combined Treatment ◽  
Random Order ◽  
Acute Effect ◽  
Parasympathetic Nerves ◽  
Before And After ◽  
Insulin Dependent

The objective was to determine the site of insulin resistance produced by intraportal atropine or surgical hepatic denervation. A modified euglycemic clamp was used in fasted cats to test the acute effect of insulin (100 mU/kg) on arteriovenous glucose gradients across the hindlimbs (mainly reflecting skeletal muscle), the guts (all organs draining into the portal vein), and the liver. Responses to insulin were determined before and after hepatic denervation and after 3 mg/kg intraportal atropine. The interventions were done in random order. Responses after either intervention were similar and were not potentiated by the combined treatment. Regional insulin resistance was assessed by comparing the change in glucose gradients in response to insulin before and after treatments. Hepatic and gut responses to insulin were unaltered, but hindlimb responses were significantly impaired after denervation or atropine. We speculate that the hepatic parasympathetic nerves regulate release of a liver-generated factor that selectively controls insulin effectiveness in skeletal muscle. This mechanism may be involved with insulin resistance in non-insulin-dependent diabetes and chronic liver disease.

scholarly journals Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor

1999 ◽  
Vol 7 (3) ◽  
pp. E6
Author(s):  
Vivek Mehta ◽  
Murray Hong ◽  
Julian Spears ◽  
Ivar Mendez
Keyword(s):  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Fetal Tissue ◽  
Cell Number ◽  
Genetically Engineered ◽  
Nigrostriatal Pathway ◽  
Behavioral Recovery ◽  
Additional Improvement ◽  
6 Hydroxydopamine

The goal of this study was to investigate the ability of fetal dopaminergic neurons to improve complex sensorimotor behavior. The authors obtained ventral mesencephalic tissue from 14-day-old rat fetuses. The cells were exposed to glial cell line-derived neurotrophic factor (GDNF) prior to transplantation into rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway. Animals that received 400,000 cells exposed to GDNF demonstrated significant improvement in contralateral forelimb function and showed improvement in rotational behavior faster than animals that received cells not exposed to GDNF. Increasing the number of implanted cells to 800,000 exposed to GDNF did not result in any additional improvement in functional recovery. As neural grafting procedures in the nervous system evolve and genetically engineered cells or stem cells replace fetal tissue, crucial questions about cell number and trophic regulation will need to be addressed. This study demonstrates that grafting of 400,000 cells exposed to GDNF before transplantation has a beneficial effect in the restoration of complex sensorimotor behavior.

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