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C V Borlongan

Publications and source records attributed to C V Borlongan.

At least 19 recordsLinked to original sources
PubMed2003

Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport.

One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B(2) bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.

Animals↗
PubMed2003

Melatonin-secreting pineal gland: a novel tissue source for neural transplantation therapy in stroke.

Chronic systemic melatonin treatment attenuates abnormalities produced by occlusion of middle cerebral artery (MCA) in adult rats. Because the pineal gland secretes high levels of melatonin, we examined in the present study whether transplantation of pineal gland exerted similar protective effects in MCA-occluded adult rats. Animals underwent same-day MCA occlusion and either intrastriatal transplantation of pineal gland (harvested from 2-month-old rats) or vehicle infusion. Behavioral tests (from day of surgery to 3 days posttransplantation) revealed that transplanted stroke rats displayed significantly less motor asymmetrical behaviors than vehicle-infused stroke rats. Histological analysis at 3 days posttransplantation revealed that transplanted stroke rats had significantly smaller cerebral infarction than vehicle-infused rats. Additional experiments showed that pinealectomy affected transplantation outcome, in that transplantation of pineal gland only protected against stroke-induced deficits in stroke animals with intact pineal gland, but not in pinealectomized stroke rats. Interestingly, nonpinealectomized vehicle-infused stroke rats, as well as pinealectomized transplanted stroke rats, had significantly lower melatonin levels in the cerebrospinal fluid than nonpinealectomized transplanted stroke rats. We conclude that intracerebral transplantation of pineal gland, in the presence of host intact pineal gland, protected against stroke, possibly through secretion of melatonin.

Animals↗
PubMed2001

Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.

Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.

Animals↗
PubMed2001

Trophic factor secreting kidney cell lines: in vitro characterization and functional effects following transplantation in ischemic rats.

Several kidney cell lines were investigated for their ability to produce glial cell line-derived neurotrophic factor (GDNF). Cell line-conditioned medium was analyzed using ELISA and two cell lines were identified which produce GDNF in physiologically active concentrations. ELISA analyses revealed that conditioned medium from these two cell lines also contained PDGF, bFGF, TGFbeta1 and TGFbeta2. Both of these cell lines were then transplanted into the striatal penumbra of rats, 1 h following middle cerebral artery occlusion. Behavioral testing revealed that both cell lines reduced the deficit associated with cerebral ischemia and reduced the infarct volume relative to controls. Reduction of infarct volume was likely achieved by the action of GDNF and/or other growth factors produced by the cells.

Animals↗
PubMed2001

Involvement of GDNF in neuronal protection against 6-OHDA-induced parkinsonism following intracerebral transplantation of fetal kidney tissues in adult rats.

Exogenous application of transforming growth factors-beta (TGF beta) family proteins, including glial cell line-derived neurotrophic factor (GDNF), neurturin, activin, and bone morphogenetic proteins, has been shown to protect neurons in many models of neurological disorders. Finding a tissue source containing a variety of these proteins may promote optimal beneficial effects for treatment of neurodegenerative diseases. Because fetal kidneys express many TGF beta trophic factors, we transplanted these tissues directly into the substantia nigra after a unilateral 6-hydroxydopamine lesion. We found that animals that received fetal kidney tissue grafts exhibited (1) significantly reduced hemiparkinsonian asymmetrical behaviors, (2) a near normal tyrosine hydroxylase immunoreactivity in the lesioned nigra and striatum, (3) a preservation of K(+)-induced dopamine release in the lesioned striatum, and (4) high levels of GDNF protein within the grafts. In contrast, lesioned animals that received grafts of adult kidney tissues displayed significant behavioral deficits, dopaminergic depletion, reduced K(+)-mediated striatal dopamine release, and low levels of GDNF protein within the grafts. The present study suggests that fetal kidney tissue grafts can protect the nigrostriatal dopaminergic system against a neurotoxin-induced parkinsonism, possibly through the synergistic release of GDNF and several other neurotrophic factors.

Age Factors↗
PubMed2000

Motor activity-mediated partial recovery in ischemic rats.

Spontaneous partial recovery in motor and/or cognitive dysfunctions in stroke patients has been documented, but the factors that affect such functional improvement have not been well elucidated. The present study demonstrates that repeated behavioral testing (daily or once a week over a period of 4 weeks) promoted partial recovery from motor asymmetry in adult ischemic rats. In contrast, ischemic animals that were only tested once every 2 weeks or once after 4 weeks did not show such partial recovery. These results suggest that repeated behavioral testing (i.e., increased use of the ischemia-affected limbs and body parts) may contribute to partial recovery of motor deficits following an experimental stroke, even in the absence of pharmacological therapeutic intervention.

Animals↗
PubMed2000

Treatment with delta opioid peptide enhances in vitro and in vivo survival of rat dopaminergic neurons.

A major problem in neural transplantation therapy is poor survival of grafted cells, which may be due to low cell viability prior to transplantation or scarce trophic factors available to the cells following transplantation. Recently, the delta enkephalin analogue [D-Ala(2),D-Leu(5)]-enkephalin (DADLE) has been demonstrated to protect against, as well as to reverse methamphetamine-induced loss of dopamine transporters. Here, we show that pretreatment with DADLE (0.0025, 0.005, 0.01 g/ml) dose-dependently enhanced cell viability of cultured primary rat fetal mesencephalic cells. In addition, DADLE administration in adult rats (4 mg/kg every 2 h, 4 injections, i.p.) prior to 6-hydroxydopamine lesions of the medial forebrain bundle, significantly reduced the severity of loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra 1 month post-lesion. This is the first report suggesting that DADLE can be used as a supplement factor for improving the cell viability of fetal mesencephalic cells and as a protective agent against neurotoxicity in a Parkinson's disease model.

Adrenergic Agents↗
PubMed2000

Artificial lighting conditions and melatonin alter motor performance in adult rats.

Entrained circadian rhythms may modulate many behavioral activities of animals and humans. In the present study, we examined whether lighting conditions and melatonin treatment participate behaviorally in the entrainment of circadian rhythms in the rodent. In experiment one, Sprague-Dawley rats were introduced to the Rotorod test apparatus at nighttime or daytime and either with the lights on (4 lux) or in the dark. During nighttime tests, the exposure of rats to dark or light condition did not alter mean rev./min or length of times spent on the Rotorod. Interestingly, during daytime tests, animals exposed to light condition displayed significantly reduced mean rev./min (7.95 +/- 1.68), as well as length of time on the Rotorod (41.07 +/- 3.45 s) compared with their performance in the dark condition (mean rev./min, 11.16 +/- 1.52; length of time spent on the Rotorod, 66.94 +/- 6.15 s). In experiment two, treatment with melatonin (1.5 mg/kg, orally administered at 1 h prior to testing) in animals introduced to the daytime test with exposure to light condition, restored the rev./min (12.90 +/- 1.26) and the time spent on the Rotorod (63.21 +/- 2.73 s) to near normal levels. Thus, we demonstrated here that exposure of nocturnal animals to their preferred dark condition and treatment with melatonin could enhance motor coordination.

Animals↗
PubMed2000

Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats.

Cyclosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system.

Animals↗
PubMed2000

Hyperbaric oxygen therapy for treatment of postischemic stroke in adult rats.

The efficacy of hyperbaric oxygen (HBO) therapy for treatment of stroke remains to be validated in the laboratory. We report here that adult rats subjected to occlusion of the middle cerebral artery and subsequently exposed to HBO (3 atm, 2 x 90 min at a 24-h intervals; animals terminated shortly after the second treatment) or hyperbaric pressure (HBP; 3 atm, 2 x 90 min at a 24-h interval; animals terminated shortly after the second treatment) immediately after the ischemia or after a 60-min delay generally displayed recovery from motor deficits at 2.5 and 24 h of reperfusion, as well as a reduction in cerebral infarction at 24 h of reperfusion compared to ischemic animals subjected to normal atmospheric pressure. While both HBO and HBP treatments promoted beneficial effects, HBO produced more consistent protection than HBP. Treatment with HBO immediately or 60 min after reperfusion equally produced significant attenuations of cerebral infarction and motor deficits. In contrast, protective effects of HBP treatment against ischemia were noted only when administered immediately after ischemia, which resulted in a significantly reduced infarction volume, but only produced a trend toward decreased behavioral deficits. The present results demonstrate that HBO and, to some extent, HBP reduced ischemic brain damage and behavioral dysfunctions.

Age Factors↗
PubMed2000

Restoration of function by neural transplantation in the ischemic brain.

Stroke remains a major brain disorder that often renders patients severely impaired and permanently disabled. There is no available treatment for reversing these deficits. Hippocampal, striatal and cortical grafting studies demonstrate that fetal cells/tissues, immortalized cells, and engineered cell lines can survive grafting into the ischemic adult brain, correct neurotransmitter release, establish both afferent and efferent connections with the host brain, and restore functional and cognitive deficits in specific models of stroke. The success of neural transplantation depends on several factors: the stroke model (location, extent, and degree of infarction), the donor cell viability and survival at pre- and post-transplantation, and the surgical technique, among others. Further exploitation of knowledge of neural transplantation therapy already available from our experience in treating Parkinson's disease needs to be critically considered for stroke therapy. While the consensus is to create a functional neuronal circuitry in the damaged host brain, there is growing evidence that trophic action of the grafts and host, as well as exogenous application of trophic factors may facilitate functional recovery in stroke. Current treatment modules, specifically that of rehabilitative medicine, should also be explored with neural transplantation therapy. However, validation of neural transplantation and any other treatment for stroke should be critically assessed in laboratory experiments and limited clinical trials. No direct treatment is recognized as safe and effective for reversing the stroke-induced brain damage and functional/cognitive deficits. The first clinical trial of neural transplantation in stroke patients is a mile-stone in stroke therapy, but subsequent large-scale trials should be approached with caution.

Animals↗
PubMed2000

Neuroprotective strategies for basal ganglia degeneration: Parkinson's and Huntington's diseases.

There are three main mechanisms of neuronal cell death which may act separately or cooperatively to cause neurodegeneration. This lethal triplet of metabolic compromise, excitotoxicity, and oxidative stress causes neuronal cell death that is both necrotic and apoptotic in nature. Aspects of each of these three mechanisms are believed to play a role in the neurodegeneration that occurs in both Parkinson's and Huntington's diseases. Strategies to rescue or protect injured neurons usually involve promoting neuronal growth and function or interfering with neurotoxic processes. Considerable research has been done on testing a large array of neuroprotective agents using animal models which mimic these disorders. Some of these approaches have progressed to the clinical arena. Here, we review neuroprotective strategies which have been found to successfully ameliorate the neurodegeneration associated with Parkinson's and Huntington's diseases. First, we will give an overview of the mechanisms of cell death and the background of Parkinson's and Huntington's diseases. Then we will elaborate on a range of neuroprotective strategies, including neurotrophic factors, anti-excitotoxins, antioxidants, bioenergetic supplements, anti-apoptotics, immunosuppressants, and cell transplantation techniques. Most of these approaches hold promise as potential therapies in the treatment of these disorders.

Animals↗
PubMed2000

Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia.

The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 micromol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 microg/ml or 100 microM) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage.

Animals↗
PubMed2000

Transplantation therapy for Parkinson's disease.

This review paper will provide an overview of the advent of neural transplantation therapy and the milestones achieved over the last 20 years for its use in treating Parkinson's disease. A discussion of technical factors that influence the outcome of neural transplantation is presented, with emphasis given on three sections dealing with immunosuppressants, alternative grafts and trophic factors which have recently been the focus of basic research and development of early phase clinical trials. Some views on the clinical assessment of transplanted Parkinson's disease patients are given at the end of the paper, with a synopsis highlighting the importance of basic research in advancing the potential clinical benefits of neural transplantation therapy in the treatment of Parkinson's disease.

Animals↗
PubMed1999

Prepro-thyrotropin-releasing hormone 178-199 exerts partial protection against cerebral ischemia in adult rats.

We examined in the present study the effects of the centrally administered prepro-thyrotropin-releasing-hormone 178-199 (prepro-TRH 178-199) on cerebral ischemia induced by ligation of the middle cerebral artery (MCA) in adult Sprague-Dawley rats. Animals were intracerebrally injected with prepro-TRH 178-199 (6 microg/kg or 200 microg/kg) or saline 1-2 h before ligation of MCA. Ischemic animals that received prepro-TRH 178-199, regardless of dosage, displayed some amelioration (20%) of motor asymmetry associated with MCA ligation, while ischemic animals that received saline continued to exhibit significant asymmetrical behaviors. Interestingly, triphenyltetrazolium chloride staining (a marker for tissue metabolic activity) revealed that four of five ischemic animals that received 200 microg/kg prepro-TRH 178-199 showed a marked reduction (90-100%) in the infarction of the frontal cortex, although the posterior sections of the cortex remained infarcted. In contrast, ischemic animals that received 6 microg/kg prepro-TRH 178-199 demonstrated infarction that did not differ in size and extent from those that received saline. Post hoc examination revealed that ischemic animals treated with 200 microg/kg prepro-TRH 178-199 had significantly lower corticosterone (CORT) levels (115+/-23 ng/ml) than ischemic animals treated with 6 microg/kg prepro-TRH 178-199 or saline (288+/-51 ng/ml). The present observation provides the first evidence that prepro-TRH 178-199 can promote neuroprotection against cerebral ischemia.

Aging↗
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↗