Search PubMed⌕ Search

Biomedical subjects

W J Freed

Publications and source records attributed to W J Freed.

At least 91 records · Page 5Linked to original sources
PubMed1988

The expression of phosphorylated neurofilament epitopes in human brains.

The expression of phosphorylated neurofilaments (PNF) epitopes in hippocampal neurons was examined in 5 cases of Alzheimer's disease and 12 brains of schizophrenic patients. A control group (n = 17) consisted of 5 brains of patients with other acute or chronic neurologic disorders and 12 brains of persons who were free of any known neurologic disease. Immunocytochemistry with monoclonal antibodies to PNF was done on formalin-fixed, paraffin sections of hippocampus. Adjacent sections were impregnated with silver. Immunoreactivity to PNF was observed in tangles and plaques of the Alzheimer's brains and also in hippocampal pyramidal cells in 6 of the 12 schizophrenic brains and in 9 of the 17 control brains (2 with neurological disorders and 7 with non-neurological diseases). The positive PNF-stained cell bodies, in silver impregnated sections, generally did not show evident neurofibrillary abnormalities. Enzymatic dephosphorylation prior to immunostaining abolished PNF reactivity. These results suggest the widespread occurrence and relative non-specificity of perikaryonal PNF immunoreactivity in human post mortem brain tissue. We could not exclude the possibility that the hippocampal and brainstem neurons are predilection sites for normal perikaryonal phosphorylation in human brain.

Adult↗
PubMed1988

Adrenal medulla grafts enhance functional activity of the striatal dopamine system following substantia nigra lesions.

Adrenal medulla grafts in the lateral ventricle reduce the behavioral manifestations of striatal dopamine depletion in an animal model of Parkinson's disease. Using microdialysis in freely moving rats, the present experiments determined that dopamine was not detectable in cerebrospinal fluid (CSF). However, adrenal medulla grafts were associated with an increase in dopamine turnover and amphetamine-stimulated striatal dopamine release was increased in animals with behaviorally effective adrenal medulla grafts. Therefore, adrenal medulla grafts increase striatal dopamine activity without an appreciable release of dopamine into the CSF. Adrenal medulla grafts also increased serum dopamine concentrations, and the increase in serum dopamine was directly correlated with the behavioral efficacy of the grafts. We suggest that dopamine, produced by adrenal medulla grafts, may gain access to the striatum via the blood supply and then leak out into the host striatum through permeable blood vessels adjacent to the graft. Through this mechanism, adrenal medulla grafts may increase functional dopaminergic activity in the striatum. These results may be important for understanding how autografts of adrenal medulla cells produce a putative alleviation of the symptoms of Parkinson's disease.

Adrenal Cortex↗
PubMed1988

Anticonvulsant activity of deaminated analogues of glutamic acid diethyl ester (GDEE).

GDEE, a specific but low-potency antagonist of the quisqualate or 'Type 2' excitatory amino acid receptor, blocks seizures induced by homocysteine and quisqualic acid. Deaminated analogues of GDEE were examined for anticonvulsant activity in mice, for the purpose of determining the structural properties of GDEE required for anticonvulsant activity. The deaminated derivative of GDEE, diethyl glutarate (5 carbon chain) inhibited homocysteine thiolactone (HTL)-induced seizures with an ED50 of 533 mg/kg. A similar compound with carbon chain length increased by two (diethyl pimelate; 7 carbons) was less effective. Decreases or further increases in carbon chain length resulted in a nearly complete loss of activity. Dimethyl glutarate (5 carbons) and dimethyl adipate (6 carbons) were similar to diethyl glutarate in potency, blocking HTL-induced seizures with ED50s of about 625 and 540 mg/kg, respectively. Diethyl ethylmalonate, diethyl maleate, and diethyl fumarate were much less effective. Diethyl glutarate, but not diethyl succinate (4 carbons), blocked seizures induced by intracerebral quisqualic acid. None of the agents tested blocked pentylenetetrazole-induced seizures. Thus a number of deaminated structural variants of GDEE have anticonvulsant activity equal to that of GDEE. The amino group of GDEE appears therefore to be irrelevant for its anticonvulsant effect.

Animals↗
PubMed1988

Cortical lesions increase reinnervation of the dorsal striatum by substantia nigra grafts.

Effects of aspiration lesions of the cerebral cortex on intraventricular substantia nigra grafts were investigated. Increased reinnervation of the dorsal striatum was observed in animals with cortical aspirations. This reinnervation was confined to the dorsal one-fourth of the striatum, immediately underneath the cortical lesions. The increased reinnervation of the striatum by substantia nigra grafts in animals with cortical lesions is suggested to be related either to secretion of neurotrophic substances by the injured brain tissue or to removal of competition between corticostriatal inputs and graft-derived neurites for synaptic contacts.

Animals↗
PubMed1988

D-dopa and L-dopa similarly elevate brain dopamine and produce turning behavior in rats.

In the intact rat, intragastric administration of D-dihydroxyphenylalanine (D-DOPA) together with carbidopa (alpha-methyldopa hydrazine, a peripheral dopadecarboxylase inhibitor) increased striatal dopamine concentration to the same extent as a similar treatment with L-DOPA plus carbidopa. In rats with unilateral 6-hydroxydopamine-induced lesions of their substantia nigra, both stereoisomers of DOPA produced significant increases in dopamine and its metabolites in the intact striata. Although dopamine concentrations in the lesioned striata did not change, a significant increase in dopamine metabolites was observed, indicating some extraneuronal formation of dopamine. These results suggest that D-DOPA can be converted to dopamine in the normal striatum as well as in the striatum devoid of dopamine nerve terminals. D- and L-DOPA produced turning behavior in unilaterally lesioned rats with a similar efficacy. The onset of turning after D-DOPA was delayed compared with L-DOPA. Turning behavior elicited by these amino acids was attributed to stimulation of supersensitive dopamine receptors in the lesioned striata by the extraneuronally formed dopamine. Preliminary results suggest that D-DOPA is converted to dopamine via transamination and/or D-amino acid oxidation to 3,4-dihydroxyphenylpyruvic acid which upon further transamination gives rise to L-DOPA and hence dopamine. The relatively fast and slow onset of stimulation of dopamine receptors L-DOPA and D-DOPA respectively suggests that the use of the racemic mixture of DOPA combined with a peripheral dopadecarboxylase inhibitor may prove useful in the treatment of parkinsonism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Cerebellar allografts in brain of quaking mice.

Fragments of normal embryonic cerebellum were transplanted into adult Quaking mice to examine using peroxidase-antiperoxidase immunocytochemistry the development of genetically normal tissue in an abnormal host environment. The Quaking mouse animals used as hosts are characterized by defective myelin associated glycoprotein. Normal characteristic expression and distribution of neurofilaments was observed in the cerebellar grafts. Nonphosphorylated epitopes of neurofilaments were seen in Purkinje cell bodies and dendrites. The phosphorylated epitopes of neurofilaments were observed in basket cell axons. Phosphorylated epitopes were also present in numerous myelinated axons, which were probably fibers from deep cerebellar nuclei. These data support the notion that neurogenesis with alternative connections can occur in transplants. Staining patterns with myelin associated glycoprotein and myelin basic protein also suggest that normal myelination occurs in grafts transplanted to the brains of Quaking mice.

Animals↗
PubMed1988

The iminodipropionitrile (IDPN)-induced dyskinetic syndrome in mice: antagonism by the calcium channel antagonist nifedipine.

Chronic administration of IDPN leads to the development of a persistent syndrome which is characterized by lateral and vertical neck dyskinesias, random circling behaviors, and locomotor hyperactivity. Although the dihydropyridine (DHP) calcium channel antagonist nifedipine inhibited all aspects of the syndrome, lateral head dyskinesias (laterocollis) and circling abnormalities were the most significantly affected signs. Dysregulation of calcium-dependent processes might be involved in the pathogenesis of the IDPN-induced dyskinetic abnormalities and clinical disorders of movement in humans.

Animals↗
PubMed1988

A comparison of intraventricular and intraparenchymal cerebellar allografts in rat brain: evidence for normal phosphorylation of neurofilaments.

Allografts of embryonic (E14-E15) rat cerebellum in adult brain were compared using the intraparenchymal and intraventricular transplantation techniques. We studied the expression and distribution of phosphorylated neurofilament (PNF) epitopes, nonphosphorylated neurofilament (nPNF) epitopes, synapse-associated antigens, glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). Both intraventricular and intraparenchymal grafts developed a clear trilaminar organization. Intraparenchymal grafts were much smaller and showed a large GFAP-positive glial scar and demyelination of host tissue. Nevertheless, myelinated fibers were present more often crossing the host-transplant border in intraparenchymal grafts. PNF and nPNF epitopes were present in both types of grafts. Staining patterns characteristic of normal rat cerebellum were seen. nPNF epitopes were present in Purkinje cell bodies and dendrites and PNF epitopes in basket cell axons surrounding Purkinje neurons. The appearance and distribution of PNF epitopes resembled that seen in normal postnatal cerebellar development and both PNF and nPNF epitopes were present at the same times in early development in both intraventricular and intraparenchymal grafts. In contrast to the situation in trauma and disease, PNF epitopes never appeared in perikarya of transplanted cerebellar neurons. The expression of synapse-associated antigens in grafted tissue was also similar to that seen in normal cerebellum.

Animals↗
PubMed1988

The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity.

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.

Animals↗
PubMed1988

Haloperidol and metabolite concentrations in the rat after concurrent isotretinoin administration: a preliminary report.

Blood and tissue haloperidol concentrations can be altered by the concurrent administration of a number of other drugs. Here we describe effects of concurrent administration of the vitamin A metabolite, isotretinoin, on haloperidol and reduced haloperidol concentrations in the rat. Isotretinoin increased the concentrations of both haloperidol and reduced haloperidol in serum, red blood cells, and brain. However, the dose dependence and degree of the effect varied significantly across tissues. Further study is called for to elucidate the interaction of neuroleptics such as haloperidol with the vitamin A acids such as isotretinoin.

Animals↗
PubMed1988

Partial reversal of the iminodipropionitrile-induced hyperkinetic syndrome in rats by alpha-tocopherol (vitamin E).

Rats were treated with the neurotoxin iminodipropionitrile (IDPN), which causes an irreversible movement disorder accompanied by axonal damage similar to that seen in vitamin E deficiency. Animals that received 2 g/kg vitamin E concurrently with 100 mg/kg IDPN for 10 days demonstrated a significantly reduced severity of IDPN-induced dyskinesia (as measured by vertical head movements) compared to animals that received IDPN alone. When animals were treated with 100 mg/kg IDPN for 10 days and then given either 2 g/kg vitamin E or an equivalent volume of sesame oil for 7 days, vitamin E produced a significant reduction in the severity of IDPN-induced dyskinesia. In both experiments, locomotor activity was unchanged by vitamin E. These data suggest a possible involvement of free radical formation in the neurotoxicity of IDPN.

Animals↗
PubMed1987

Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra.

This study examined the effects of continuously supplied dopamine delivered directly into the dopamine-deficient striatum. Rats received unilateral lesions of the substantia nigra by stereotaxic administration of 6-hydroxydopamine and were tested for apomorphine-induced rotational behavior and general activity. Osmotic mini-pumps were filled with dopamine in various concentrations, implanted subcutaneously and connected to a cannula implanted directly into the striatum. The system delivered solution at a rate of .5 microliter/hr for two weeks. Dopamine in a dosage of 0.5 microgram/per hour reduced apomorphine-induced rotational behavior by a mean of 52 +/- 5.8% (mean +/- SEM, n = 20) with a maximal individual decrease of 99%. There was no change in general activity or increase in stereotyped behavior. Infusions of vehicle solutions did not decrease rotational behavior. Spread of the infused dopamine and its metabolites was estimated by adding 3H-dopamine to the pumps in tracer quantities. Radioactivity was highly concentrated at the infusion site and decreased rapidly within a few mm from the infusion site. Continuous infusion methods may eventually prove to be effective in the treatment of nigro-striatal degenerative disease.

Animals↗
PubMed1987

Induction of seizures in mice by intracerebroventricular administration of the calcium channel agonist BAY k 8644.

The calcium channel agonist BAY k 8644 was used to investigate the role of the calcium ion (Ca2+) in epileptogenesis. Intracerebroventricular administration of the compound induced murine seizures that were reversed by calcium channel inhibitors (CCIs) but not by anticonvulsants such as carbamazepine, pentobarbital, and diazepam. The seizures were exacerbated by phenytoin and valproic acid. Chronic administration of CCI's, previously shown to produce down-regulation of the binding of the CCI [3H]nitrendipine, resulted in augmentation of BAY k 8644-induced seizures.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Brain tissue transplantation in neonatal rats prevents a lesion-induced syndrome of adipsia, aphagia and akinesia.

Previous experiments have proven brain tissue transplantation effective in reversing lesion-induced behavioral deficits in mature rats. This study reversed the usual experimental paradigm, so that fetal substantia nigra was transplanted into intact neonatal rats and allowed to mature in the host brain. Upon maturation substantia nigra lesions were made bilaterally to reveal the functional contribution of the transplanted tissue. In control animals these lesions depleted striatal dopamine, producing rigidity, poverty of movement and abnormal posture comparable to Parkinson's disease in the human; cessation of feeding and drinking led to progressive weight loss and death. In contrast, fetal substantia nigra transplanted into the neonatal rat became well-integrated in the host brain and was shown to protect the animal from this syndrome produced by subsequent substantia nigra lesions. We suggest that transplantation in these neonatal rats was performed during a crucial period of synaptogenesis, an environment particularly favorable to host-transplant interaction.

Animals↗