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C V Borlongan

Publications and source records attributed to C V Borlongan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cyclosporine-A reduces spontaneous place preference in adult rats.

Cyclosporine-A (CsA) and its analogues have been shown to directly alter locomotor activity. The present study examined CsA effects on spontaneous preferential behavior in adult rats, using a two-shuttle compartment box. The initial preference (>450 s staying time) of the animal for one compartment was measured at pre-conditioning session (900 s). During conditioning session (one 60-min session per day for 6 consecutive days), the animal was alternately injected with CsA (5, 10, 20 and 30 mg/kg per day, i.p.) and vehicle, and its movement restricted to the preferred compartment and the other compartment, respectively. At post-conditioning session (900 s), animals were allowed to freely explore the box. Animals that were treated with 10 mg/kg CsA significantly spent less staying time in the preferred compartment, while those that received other CsA doses displayed a trend of decreased staying time in the preferred compartment. The present data demonstrate that CsA antagonized the spontaneous preferential behavior of animals, and warrant investigations on the drug's utility in altering other preferential behaviors (e.g. drug addiction, alcohol abuse).

Animals↗
PubMed1999

Lithium chloride induces the expression of tyrosine hydroxylase in hNT neurons.

In the present study, several doses of lithium chloride were tested for their ability to induce the expression of tyrosine hydroxylase (TH) in neurons derived from a human teratocarcinoma cell line (hNT) after 5 and 10 days in vitro (DIV). Following immunocytochemical staining for tyrosine hydroxylase, the percentage of TH-positive neurons was determined and morphometric analysis, including mean soma profile area and neuritic length, was performed. hNT neurons responded to lithium treatment in a dose-dependent manner. In 5 DIV, the most effective dose of lithium chloride (1.0 mM) increased the number of TH-positive neurons approximately sixfold. In addition, both TH-positive hNT neuron mean soma profile area and neurite length were significantly larger than controls by 60 and 70%, respectively. Moreover, even after withdrawal of lithium chloride on day 5, the number of TH-positive neurons in 10 DIV cultures remained significantly increased. These data suggest that hNT cells are indeed responsive to lithium exposure and may serve as a continual source of TH-expressing neurons in new therapeutic approaches to degenerative brain disease.

Cell Differentiation↗
PubMed1999

Neural transplantation of human neuroteratocarcinoma (hNT) neurons into ischemic rats. A quantitative dose-response analysis of cell survival and behavioral recovery.

Transplantation of fetal neuronal tissue has been used successfully to ameliorate symptoms of neurodegenerative disease in animals and humans. This technique has recently been extended as an experimental treatment for ischemic brain damage. However, due to ethical issues with the use of fetal cells for the treatment of any human disease, there has been a concerted effort to find alternative graft sources for neural transplantation. The human neuroteratocarcinoma neuron cell is derived from an embryonal teratocarcinoma cell line that can be differentiated into post-mitotic neurons. Neural transplantation of human neuroteratocarcinoma neurons has recently been shown to produce behavioral amelioration of symptoms in rats with ischemia-induced injury. The present study was undertaken to: (i) determine the minimum effective number of transplanted human neuroteratocarcinoma neurons required for amelioration of ischemia-induced behavioral dysfunction; and (ii) quantify the survival of human neuroteratocarcinoma neurons in vivo. Transplants of 0, 5, 10, 20, 40, 80 or 160 x 10(3) human neuroteratocarcinoma neurons were made into rats that sustained ischemic damage. Animals that received 40, 80 or 160 x 10(3) human neuroteratocarcinoma neurons demonstrated a dose-dependent improvement in performance of both the passive avoidance and elevated body swing tests. At the conclusion of behavioral testing, human neuroteratocarcinoma neurons were identified in paraffin sections with human neural cell adhesion molecule MOC-1 and human neurofilament antibodies. Transplants of 80 or 160 x 10(3) human neuroteratocarcinoma neurons demonstrated a 12-15% survival of human neuroteratocarcinoma neurons in the graft, while transplants of 40 x 10(3) human neuroteratocarcinoma neurons demonstrated a 5% survival. Transplantation of human neuroteratocarcinoma neurons ameliorated behavioral deficits produced by ischemic damage. The human neuroteratocarcinoma neuron, additionally, showed greater survival than that reported for fetal cells when transplanted into the brain. Therefore, this readily available cell may prove to be an excellent candidate for the treatment of ischemic damage in human patients.

Animals↗
PubMed1999

Transplantation of fetal kidney tissue reduces cerebral infarction induced by middle cerebral artery ligation.

The authors, and others, have recently reported that intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) or osteogenic protein-1 protects against ischemia-induced injury in the cerebral cortex of adult rats. Because these trophic factors are highly expressed in the fetal, but not adult, kidney cortex, the possibility that transplantation of fetal kidney tissue could serve as a cellular reservoir for such molecules and protect against ischemic injury in cerebral cortex was examined. Fetal kidneys obtained from rat embryos at gestational day 16, and adult kidney cortex, were dissected and cut into small pieces. Adult male Sprague-Dawley rats were anesthetized with chloral hydrate and placed in a stereotactic apparatus. Kidney tissues were transplanted into three cortical areas adjacent to the right middle cerebral artery (MCA). Thirty minutes after grafting, the right MCA was transiently ligated for 90 minutes. Twenty-four hours after the onset of reperfusion, animals were evaluated behaviorally. It was found that the stroke animals that received adult kidney transplantation developed motor imbalance. However, animals that received fetal kidney grafts showed significant behavioral improvement. Animals were later sacrificed and brains were removed for triphenyltetrazolium chloride staining, Pax-2 immunostaining, and GDNF mRNA expression. It was noted that transplantation of fetal kidney but not adult kidney tissue greatly reduced the volume of infarction in the cerebral cortex. Fetal kidney grafts showed Pax-2 immunoreactivity and GDNF mRNA in the host cerebral cortex. In contrast, GDNF mRNA expression was not found in the adult kidney grafts. Taken together, our data indicate that fetal kidney transplantation reduces ischemia/reperfusion-induced cortical infarction and behavioral deficits in adult rats, and that such tissue grafts could serve as an unique cellular reservoir for trophic factor application to the brain.

Animals↗
PubMed1998

Early assessment of motor dysfunctions aids in successful occlusion of the middle cerebral artery.

Occlusion of the rodent middle cerebral artery by embolism, using an intraluminal filament, produces behavioral alterations which resemble many symptoms associated with stroke. This model has been used to examine treatment interventions for the disease, however, variable success rate in completely blocking the middle cerebral artery may present inconclusive interpretation of the data. To detect successful occlusion of the middle cerebral artery, we demonstrate here sensitive and reliable behavioral parameters including the elevated body swing test, the postural tail-hang test, the spontaneous rotational test, and the forelimb akinesia test. These assays provide a criterion for identifying animals with incomplete occlusion which could promote host-related spontaneous recovery and might confound true effects of experimental therapies on ischemia-induced dysfunctions. From a practical standpoint, the early reliable identification of partial cerebral ischemia aids in immediate and efficient adjustments of the surgical procedure to create a complete and stable ischemia stroke animal model.

Animals↗
PubMed1998

Cerebral ischemia and CNS transplantation: differential effects of grafted fetal rat striatal cells and human neurons derived from a clonal cell line.

Stroke mortality has declined over recent decades, prompting a demand for the development of effective rehabilitative therapies for stroke survivors. This effort has been facilitated by significant progress in replicating the behavioral and neuropathological changes of authentic human cerebral ischemia using relevant animal models. Since the rodent model of middle cerebral artery occlusion mimics several motor abnormalities seen in clinical cerebral ischemia, we have utilized this model to investigate treatment strategies for stroke. The present study explored the potential benefits of neural transplantation of fetal rat striatal cells or human neurons derived from a clonal embryonal carcinoma cell line to correct the abnormalities associated with cerebral ischemia. We report here that ischemia-induced behavioral dysfunctions were ameliorated by the neural grafts as early as 1 month post-transplantation. Of note, transplantation of human neurons induced a significantly more robust recovery than fetal rat striatal grafts. Thus, the logistical and ethical concerns about the use of fetal striatal cells for transplantation therapy can be eliminated by exploiting cell line-derived human neurons as alternative graft sources. Transplantation of human neurons has a therapeutic potential for treatment of behavioral deficits associated with cerebral ischemia.

Animals↗
PubMed1998

Viability and survival of hNT neurons determine degree of functional recovery in grafted ischemic rats.

We recently reported behavioral improvements following intrastriatal transplantation of cryopreserved cultured human neuroteratocarcinoma-derived cells (hNT neurons) in rats with cerebral ischemia induced by occlusion of the middle cerebral artery. In the present study, the viability and survival of hNT neurons were evaluated immediately prior to the transplantation surgery and at 3 months post-transplantation in ischemic rats. Cryopreserved hNT neurons were routinely thawed, and trypan blue exclusion viability counts revealed 52-95% viable hNT neurons before transplantation. Monthly behavioral tests, starting at 1 month and extending to 3 months post-transplantation, revealed that ischemic animals that were intrastriatally transplanted with hNT neurons (approximately 40000) and treated with an immunosuppressive drug displayed normalization of asymmetrical motor behavior compared with ischemic animals that received medium alone. Within-subject comparisons of cell viability and subsequent behavioral changes revealed that a high cell viability just prior to transplantation surgery correlated highly with a robust and sustained functional improvement in the transplant recipient. Furthermore, histological analysis of grafted brains revealed a positive correlation between number of surviving hNT neurons and degree of functional recovery. In concert with similar reports on fetal tissue transplantation, we conclude that high cell viability is an important criterion for successful transplantation of cryopreserved neurons derived from cell lines to enhance graft-induced functional effects.

Animals↗
PubMed1998

Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats.

This study was designed to explore the efficacy of a human clone cell line as an alternative neural graft source and to validate the practice of cryopreservation and xenografting as logistical approaches toward conducting neural transplantation. We investigated the biological effects of transplanting cultured human neurons (NT2N cells) derived from a well-characterized embryonal carcinoma cell line into the brains of rats subjected to transient, focal cerebral ischemia induced by embolic occlusion of the middle cerebral artery. At 1 month and extending throughout the 6-month posttransplantation test period, ischemic animals that were transplanted with NT2N cells and treated with an immunosuppressive drug displayed a significant improvement in a passive avoidance task as well as a normalization of asymmetrical motor behavior compared to ischemic animals that received rat fetal cerebellar cell grafts or vehicle alone. Remarkably, cryopreserved NT2N cell grafts compared with fresh NT2N cell grafts, remained viable in the immunosuppressed rat brain and effective in producing behavioral recovery in immunosuppressed ischemic animals. The long-term viability of cryopreserved NT2N cell xenografts in vivo and their sustained effectiveness in promoting behavioral recovery suggest potential utilization of xenografting and cryopreservation as useful protocols for establishing clone cell lines as graft source in neural transplantation therapies for central nervous system disorders.

Animals↗
PubMed1998

Intrastriatal transplantation of rat adrenal chromaffin cells seeded on microcarrier beads promote long-term functional recovery in hemiparkinsonian rats.

Possible biologic treatments for Parkinson's disease, a disorder caused by the deterioration of dopaminergic neurons bridging the nigrostriatal system, have recently focused on fetal cell transplantation. Because of ethical and tissue availability issues concerning fetal cell transplantation, alternative cell sources are being developed. The adrenal medulla has been used as a cell transplant source because of the capacity of the cells to provide catecholamines and to transform into a neuronal phenotype. However, adrenal tissue transplants have shown limited success, primarily because of their lack of long-term viability. Recently, seeding adrenal chromaffin cells on microcarrier beads has been shown to enhance the cell viability following neural transplantation. In the present study, we further investigated whether transplantation of rat adrenal chromaffin cells seeded on microcarrier beads into the striatum of 6-hydroxydopamine-induced hemiparkinsonian rats would result in a sustained functional recovery. Behavioral tests using the apomorphine-induced rotational and elevated body swing tests up to 12 months posttransplantation revealed a significant behavioral recovery in animals that received adrenal chromaffin cells seeded on microcarrier beads compared to animals that received adrenal chromaffin cells alone, medium alone, or beads alone. Histological examination of tissue at 14 months posttransplantation revealed evidence of tyrosine hydroxylase-positive cells and an on-going glial response in animals transplanted with adrenal chromaffin cells seeded on microcarrier beads, in contrast to absence of such immunoreactive responses in the other groups. These findings support a facilitator role for microcarrier beads in transplantation of adrenal chromaffin cells or other cells that are easily rejected by the CNS.

Adrenal Glands↗
PubMed1998

Estrogen protects against while testosterone exacerbates vulnerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid.

Gender differences in the vulnerability of the lateral striatal artery (1STR artery) to systemic intoxication with 3-nitropropionic acid (3-NPA, succinate dehydrogenase inhibitor) were studied. Subcutaneous injection of 3-NPA (20 mg/kg once a day for 2 days) induced striatal selective lesions in half of male rats associated with motor symptoms (rolling, paddling, recumbency, etc) while female rats were resistant. Lesions were located in the lateral striata and characterized by astroglial necrotic cell death, enhanced immunoreaction to factor VIII-related antigen, edema, extravasation of IgG and sometimes bleeding. The motor and histological disturbances were highly sex-dependent and modulated by changes in hormonal levels. Males were more susceptible than females. Castration had little effect but ovariectomy enhanced the vulnerability. Replacement therapy with testosterone increased while estradiol or tamoxifen suppressed the vulnerability in ovariectomized females. Investigation of the arterial architecture of the brain often revealed rectangular and acute angled branchings in the centrolateral striatum where the ISTR artery feeds. A parallel in vitro toxicity study demonstrated that an extreme Ca++ overload and a strong cellular swelling resulted in astrocytic cell death. Data suggest that 1STR artery and astrocytes are highly vulnerable to 3-NPA intoxication in males. The greater vulnerability of the ISTR artery may contribute to the pathogenesis of neurodegenerative diseases, striatal bleeding, etc. Protective effects of estrogen and tamoxifen may mediate gender differences often observed in these disorders and suggest their potential use as therapeutic agents for these disorders.

Animals↗
PubMed1998

Chronic cyclosporine-A injection in rats with damaged blood-brain barrier does not impair retention of passive avoidance.

Recently, we demonstrated that chronic administration of immunosuppressant drug, cyclosporine-A (CsA), does not produce impairment in memory retention of a passive avoidance task in normal adult rats. Since CsA has been used as an adjunctive therapy to avoid xenograft rejection inherent in neural transplantation therapy for neurodegenerative disorders, we replicated our previous study in animals with damaged blood-brain barrier (BBB) simulating that of the neural transplantation protocol. Adult rats with damaged BBB that received either chronic CsA (5, 10, and 20 mg/kg) or vehicle injection did not differ significantly in their memory retention of the passive avoidance task that rewarded 'less mobile activity', in that animals avoided electric shock when they restrained their movements within the safe compartment. General spontaneous locomotor activity also was not altered by CsA, except in animals that received 20 mg/kg, which displayed significant hypoactivity at later post-injection periods of CsA. The absence of potentiation of retention of the passive avoidance task in all CsA-treated animals, including the hypoactive ones, suggests that locomotor activity did not interfere with cognitive behavior. The present results confirm our previous findings that the therapeutic dosage (10 mg/kg) of CsA used for neural transplantation does not produce visible deleterious effects on the performance of memory retention task in immunosuppressed rats with damaged BBB.

Animals↗
PubMed1997

Chronic administration of cyclosporine A does not impair memory retention in rats.

Cyclosporine A (CsA) is the treatment of choice for patients undergoing organ as well as neural transplantation. CsA immunosuppression is associated with neurological and motor alterations in transplant recipients as well as in normal or hemiparkinsonian rats. We investigated possible impairments of memory retention in CsA-treated rats to determine direct effects of CsA on the dementing illness inherent in most neurodegenerative disorders. Rats receiving chronic treatment with CsA at a dose of 10 mg kg-1, i.p., daily for 26 days, as used in neural transplants for animal models of neurodegenerative disorders did not significantly differ from vehicle-treated rats, and even appeared slightly improved, in retention of a passive avoidance task. This present observation parallels recent studies demonstrating 'neuroprotective' effects of CsA in addition to its immunosuppressive effects.

Animals↗
PubMed1997

Survival of rat and porcine Sertoli cell transplants in the rat striatum without cyclosporine-A immunosuppression.

The use of cyclosporine-A (CsA) immunosuppression for neural transplantation has become the treatment of choice for ameliorating host-graft rejection responses in human and animal transplant studies. However, the cytotoxic effects of CsA have warranted a search for alternative methods of protecting neural transplants. Sertoli cells produce an immunosuppressant factor, Fas ligand (Fas-L), that may provide the testis with its immunoprivileged status. Therefore, it has recently been suggested that these cells may be useful in producing localized immunosuppression for transplants. If Sertoli cells do produce localized immunosuppression, then it should be possible to successfully transplant Sertoli cells without additional immunosuppression following transplant surgery. The present study was undertaken to determine whether rat or porcine Sertoli cells transplanted into rat brain would survive for an extended period of time without CsA immunosuppression. Isolated rat or porcine Sertoli cells prelabeled with DiI were transplanted into normal rat brain. We report that both rat Sertoli cell allografts and porcine Sertoli cell xenografts survived for at least 2 months posttransplantation into the rat brain without CsA immunosuppression, indicating that these grafts were capable of producing sufficient localized immunosuppression to survive at the site of transplant without additional systemic immunosuppression.

Animals↗
PubMed1997

Intracerebral transplantation of testis-derived sertoli cells promotes functional recovery in female rats with 6-hydroxydopamine-induced hemiparkinsonism.

Recently, we demonstrated amelioration of behavioral deficits associated with 6-hydroxydopamine-induced hemiparkinsonism by transplanting rat testis-derived Sertoli cells into adult male rat brains. In the present study, we used adult female hemiparkinsonian rats to investigate whether the beneficial effects of transplantation of Sertoli cells may be differentially affected by gender of the animal transplant recipient. At 1 month posttransplantation, animals transplanted with Sertoli cells showed functional recovery as revealed by significant reductions in apomorphine-induced rotational behavior and asymmetrical elevated body swing behavior. Control animals that received medium alone did not display any visible behavioral recovery. These results suggest that transplantation of Sertoli cells is not male hormone-dependent and further support the use of these cells as a graft source for Parkinson's disease and other neurological disorders.

Animals↗
PubMed1997

Neural transplantation as an experimental treatment modality for cerebral ischemia.

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.

Animals↗
PubMed1997

Footshock facilitates discrimination of stimulus properties of morphine.

We previously reported that stimulus properties of morphine can be assessed in a passive avoidance conditioning paradigm using a single dosing discrimination test. In this behavioral task, mice were trained to avoid electric footshock in a two-compartment shuttle-box by pairing morphine with shock in one compartment and saline with shock in the other compartment. In subsequent shock-free tests, animals can discriminate very well between saline and low doses of morphine on the one hand, and higher doses of morphine (close to that given during conditioning) on the other. Since only a single dose of morphine was presented on each test day, several days were needed to test different doses of the drug. We thus explored improving this technique by presenting different doses of morphine in a single day (cumulative dosing discrimination test). However, the animals did not dicriminate successfully between saline and morphine. Past studies have reported that mice utilize a "win-stay, lose-shift" strategy in their discrimination behavior. We hypothesized that the cumulative dosing test may have been subject to a "win-stay" bias. Accordingly, the initial exposure to the non-shock, i.e. saline, compartment promoted the animals to stay in this compartment until shock was administered. With the shock withheld throughout the test session, the "win-stay" strategy guided the animals to persevere in staying in this compartment. To confirm our hypothesis, a "lose-shift" condition through the presentation of a mild electric footshock was introduced during the test sessions. Results revealed a successful discrimination of stimulus properties of morphine, suggesting that the "lose-shift" strategy facilitated the discrimination of stimulus properties of morphine. These observations, taken together, would imply that the "win-stay, lose-shift" strategy may interact with the discrimination of the drug effects. Furthermore, the present results support the view that maintaining the environmental conditions, i. e. presence of a mild electric shock, across conditioning and test sessions can assist animals in retention of a learned task.

Animals↗