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Biomedical subjects

T B Freeman

Publications and source records attributed to T B Freeman.

At least 55 records · Page 3Linked to original sources
PubMed1995

(-)-nicotine protects against systemic kainic acid-induced excitotoxic effects.

(-)-Nicotine was shown to produce in vivo protection against neurobehavioral effects caused by systemically administered kainic acid (KA), an excitotoxin that has been widely used to induce temporal lobe convulsions including "wet dog shakes" in experimental animals. Rats pretreated with (-)-nicotine (0.5 mg/kg sc) 15 min before receiving KA (12.0 mg/kg sc) exhibited a marked reduction (P < 0.5) in the number of wet dog shakes when compared to saline-pretreated rats. Similarly, little visible brain damage was found in the (-)-nicotine-pretreated rats, but a widespread reduction in acetylcholinesterase-positive neurons was noted in the hippocampal areas of the saline-pretreated animals. While the mechanism of neuroprotection of (-)-nicotine is still not known, these findings suggest that (-)-nicotine may act as a therapeutic agent for putative excitotoxin-mediated disorders.

Animals↗
PubMed1995

Striatal dopamine-mediated motor behavior is altered following occlusion of the middle cerebral artery.

Cerebral infarct (stroke) causes striatal damage with subsequent deterioration of sensorimotor and cognitive functions that may be mediated by the dopamine receptor system. In the present study, transient, focal ischemia was induced in Sprague-Dawley rats by middle cerebral artery occlusion. Ischemic animals exhibited significantly less dopamine antagonist (haloperidol)-induced catalepsy and more dopamine agonist (amphetamine)-induced hyperactivity than sham-operated animals. Younger ischemic animals showed more profound behavioral alteration but also displayed greater recovery over time than older ischemic animals. Histologic data revealed a lateral striatal lesion in all ischemic animals. These results place the striatal dopaminergic system as a possible strategic venue for the treatment of cerebral ischemia. In addition, aging is found to be a risk factor for stroke as noted in humans.

Animals↗
PubMed1995

Systemic 3-nitropropionic acid: behavioral deficits and striatal damage in adult rats.

Previous animal studies have demonstrated that systemic administration of 3-nitropropionic acid (3-NP) leads to neuropathological changes similar to those seen in Huntington's disease (HD). Recently, we reported hypoactivity in 6- and 10-week old rats treated with systemic 3-NP (IP, 10 mg/kg/day) once every 4 days for 28 days. Although these behavioral results seem to differ from the observed hyperactivity in most excitotoxic models of HD, 3-NP may provide a better model of juvenile onset and advanced HD. In the present study, older rats were similarly treated with 3-NP to further characterize the reported age dependency of striatal neuronal death caused by 3-NP. Hypoactivity was observed in 14- and 28-week old rats with the latter demonstrating more profound features. The present study also provided the first direct evidence of a 3-NP effect on passive avoidance behavior. Experimental and control animals showed no significant difference in daytime acquisition and retention of a passive avoidance task. However, when the retention tests were conducted during the night time (in contrast to previous daytime tests), 3-NP-treated animals exhibited significant retention deficits. In addition, the neuropathological effects of 3-NP were determined by Nissl, AChE and NADPH-diaphorase histochemistry. Metabolic activity was studied using cytochrome oxidase activity as an index. Results revealed striatal glial infiltration, loss of intrinsic striatal cholinergic neurons, but some sparing of large AChE positive neurons, minimal damage of NADPH-diaphorase-containing neurons, and very slight, if any, alterations in cytochrome oxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intrastriatal 3-nitropropionic acid: a behavioral assessment.

Systemic injections of 3-nitropropionic acid (3-NP) in Sprague-Dawley rats have led to (1) hypoactivity that resembles juvenile onset and advanced Huntington's disease (HD), and (2) impairment in contextual retention of passive avoidance. Since it has been established that 3-NP exerts its primary effects in the striatum, we selected intrastriatal injections to more thoroughly understand the direct behavioral effects of 3-NP. Each 14-week old rat received bilateral intrastriatal injections of one of the following: 500 and 750 nmol of 3-NP or vehicle (0.9% saline). At seven days following surgery, the animals were tested for spontaneous locomotor behavior and passive avoidance behavior. Results revealed deficits in both locomotor activity and passive avoidance learning. The animals injected with 500 and 750 nmol of 3-NP were significantly hypoactive compared with control animals. Similarly, the 2 groups of animals were severely impaired in the retention of passive avoidance compared with control. The 3 groups, however, did not differ in their acquisition of this learning task. Macroscopic analyses of brains of these animals revealed that 500 and 750 nmol of 3-NP caused severe loss of neuronal cell bodies and marked glial infiltration in the medial aspect of the striatum. Larger lesions showed a necrotic cavity at the injection site. In comparison with systemic administration of 3-NP, intrastriatal injections resulted in more profound hypoactivity, greater loss of passive avoidance retention, and more severe striatal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Systemic 3-nitropropionic acid: long-term effects on locomotor behavior.

Systemic administration of 3-nitropropionic acid (3-NP) results in striatal atrophy by irreversibly inhibiting the citric acid cycle, and thereby resulting in cellular ATP depletion. The neuropathological outcome following 3-NP injections is thought to resemble that seen in Huntington's disease (HD) [1]. The current study administered systemic injections in 6- and 10-week-old rats of low-dose 3-NP every other 4 days for a period of 28 days in order to investigate the effects on locomotor behavior and striatal D1 dopamine receptor binding. Experimental and control animals received intraperitoneal injections of 3-NP (10 mg/kg in 0.9% saline) and 0.9% saline, respectively. Animals were tested behaviorally prior to the first and after the last 3-NP administration. Brains were then removed and striatal tissue samples were analyzed for D1 dopamine receptor binding using [3H]SCH23390. Behaviorally, 6-week-old injected animals developed bradykinesia with no signs of stiffness or rigidity, while 10-week-old injected animals displayed an uncoordinated gait, stiffness and ventral recumbency with hind limbs extended in a rigid or fixed position. These visual observations of hypoactivity were supported by a significant decline in both experimental groups' locomotor activity as measured by Digiscan monitors. Furthermore, [3H]SCH23390 specific binding to D1 dopamine receptors revealed a small but significant decrease in 10-week-old injected animals compared to controls. These results demonstrate that both 6- and 10-week-old rats do exhibit behavioral alterations after long-term 3-NP administration, however the former may not show accompanying gross D1 receptor changes.

Aging↗
PubMed1994

Recent advances in neural transplantation. Relevance to neurodegenerative disorders.

Anatomical and behavioral characterizations of neural transplants, whether within (allograft) or across (xenograft) species, have provided evidence that the transplant survives, integrates with the host tissue, and may lead to functional recovery. Several animal models of neurodegenerative disorders demonstrate the feasibility of using neural transplantation as an alternative treatment for these human diseases. While more elaborate basic animal studies are needed, clinical trials have begun. Neural transplantation is currently used as an experimental treatment for Parkinson's disease and several investigators have suggested using the same treatment procedure for other neurodegenerative disorders, such as Huntington's and Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Cell transplantation for central nervous system disorders.

Initially, the specific aim of transplantation studies was to investigate the regenerative capabilities of the mammalian nervous system. From this underlying impetus, a myriad of knowledge, spanning from molecular biology to neurobiology, has enhanced our understanding of regeneration and the applicability of fetal tissue transplantation in treating various neurodegenerative diseases. Current evidence suggests that transplantation of fetal neural tissue ameliorates the neurobiological and behavioral changes observed in animal models of central nervous system (CNS) disorders. In light of numerous basic science studies, clinical trials have begun to evaluate the potential of neural transplantation in treating human diseases. Indeed, modest progress has been reported in the treatment of Parkinson's disease. However, whereas fetal tissue transplantation has reached considerable success, it has also been observed to produce either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Thus, while the prospects are promising, further investigations aimed at improving and refining existing transplantation paradigms are warranted before neural transplantation techniques can be of widespread value. This review article attempts to provide an overview of the neuroanatomical, neurochemical, and behavioral effects produced by transplanted fetal tissue in several animal models of CNS disorders. We have attempted to present both positive and adverse effects and to critically analyze the suitability of neural transplantation as a therapy for the various neurological disorders. In addition, alternative approaches, including the use of encapsulated neural tissue implants and genetically engineered cell lines along with their clinical potential, are discussed when appropriate.

Animals↗
PubMed1993

Behavioral effects of fetal neural transplants: relevance to Huntington's disease.

Animal models of Huntington's disease (HD) and other neurological disorders have proven useful for examining the anatomical, neurochemical, and behavioral alterations in these diseases. Investigators have taken advantage of new excitotoxic models that appear to successfully simulate the neurobiological and behavioral characteristics of HD with remarkable homology. Selective excitotoxic compounds allow for a more precise and controlled lesion with which to examine the relationship between striatal damage and behavioral abnormalities. In addition, these models provide new approaches for developing and testing various treatments for HD. Fetal neural tissue transplanted into the excitotoxin-lesioned animal can integrate with the host brain and promote neurochemical and functional recovery. Neural grafting paradigms may be viewed as potential therapies for treating neurodegenerative diseases and as aids in deciphering the regenerative mechanisms of the central nervous system. Further research is necessary, however, to determine the negative and positive effects of neural transplantation. In addition, existing behavioral models need to be refined to allow for better evaluation of the subtle topographic changes in behavior resulting from fetal tissue transplantation.

Animals↗
PubMed1991

Hepatic 5'-deiodinase activity of Japanese quail using reverse-T3 as substrate: assay validation, characterization, and developmental studies.

Using rT3 as substrate, an in vitro 5'D assay was validated for use with liver tissue from adult Japanese quail, by defining conditions under which activity is proportional to enzyme (protein) concentration and is linear with incubation time. Activity was measured as the release of 125I from labeled rT3. Using validated assay conditions we found the following 5'D characteristics: maximal activity from 10 to 50 mM dithiothreitol (cofactor), an apparent Km of 0.52 microM rT3, pH optimum of 7.6-8.5, complete inhibition by 1 mM propylthiouracil and by 1.0 mM iopanoic acid, and substrate "preference" of rT3 greater than T4 greater than T3. Based on these characterizations the quail hepatic 5'D activity is like the Type I 5'D activity found in mammalian liver and kidney and embryonic chicken liver. To determine how previous unvalidated assays, that used high tissue and relatively low substrate (T4) concentrations, influenced 5'D studies we reevaluated 5'D development using an assay validated for each developmental stage with rT3 as substrate. We found extreme quantitative differences in the activities measured and in the proportional relationships between stages, and only limited qualitative similarity in the pattern of 5'D development when unvalidated T4 assay results were compared with validated rT3 assay results. Our data in this paper show good correspondence between whole liver 5'D activity per unit body weight and plasma T3/T4 ratios for the developmental stages sampled.

Animals↗
PubMed1991

Development of dopaminergic neurons in the human substantia nigra.

A series of 29 human embryonic brains were examined in order to characterize the ontogeny of dopaminergic neurons within the developing substantia nigra. Embryos from Postconception Weeks 4.0 to 11.2 (last menstrual period 6.0-13.2) were studied. Immunohistochemical staining was performed using a polyclonal antibody to tyrosine hydroxylase. Tyrosine hydroxylase-like immunoreactivity was first seen in cells of the ventral mesencephalon at 6.5 weeks adjacent to the ventricular zone. Ventral migration of TH-positive cells began at 6.7 weeks. Neural process extension was first identified in tyrosine hydroxylase-positive neurons at 8.0 weeks. The ascending nigrostriatal bundle was also first demonstrated at 8.0 weeks. Tyrosine hydroxylase containing neurites were seen initially in the developing putamen at 9.0 weeks. Only a few tyrosine hydroxylase-positive cells remained adjacent to the ventricular zone at Week 10.0 and all had disappeared from the ventricular zone by 11.2 weeks. At this latter stage, a large number of dopaminergic cells had elaborated neural processes. The sequence of developmental events of human mesencephalic dopaminergic neurons is similar to the equivalent period of ontogeny in other mammals. The duration of the developmental period is, however, significantly protracted.

Dopamine↗
PubMed1991

Hepatic 5'-deiodination in chickens from lines selected for high and low body weight and their F1 cross.

1. Assay conditions for measuring hepatic 5'-deiodinase (5'D) activity at initial velocity, using reverse T3 as substrate, have been validated for adult chicken liver. 2. The characteristics of hepatic 5'D activity in adult chickens from lines selected for high (HW) and low (LW) juvenile body weight are similar to those in mammals and in the other birds that have been investigated. 3. Chickens from the HW line have significantly higher specific activity of hepatic 5'D, and thus potentially higher T3 production, than those from either the LW line or the F1 cross (HL) between the HW and LW lines.

Animals↗
PubMed1989

Thyroid hormones and growth patterns of embryonic and posthatch chickens from lines selected for high and low juvenile body weight.

Lines of chickens divergently selected for high (HW) or low (LW) 56-day posthatch body weight were evaluated for growth, development of small intestine, liver and pectoral muscle, and plasma T3 and T4 concentrations. Measurements were taken at 11,17, and 20 days of incubation and 5, 12, 20, 31, and 61 days posthatch. HW chicks and their organs were consistently larger than LW chicks and their organs from day 17 of incubation onward, and followed growth patterns characteristic of these lines. Significant line by age interactions indicated that chickens divergently selected for juvenile body weight had different temporal patterns for plasma T3 and for T4 from 11 days of incubation to 61 days posthatch. There were no differences between males and females within each line for either T3 or T4. There were no simple relationships between the patterns of plasma concentrations of either T3 or T4 and the pattern of growth of the body or the organs studied.

Animals↗