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N H Neff

Publications and source records attributed to N H Neff.

At least 19 recordsLinked to original sources
PubMed1997

Cholinergic deficits in aged rat spinal cord: restoration by GM1 ganglioside.

Cholinergic neurons of spinal cord are central for the processing of motor, autonomic, and sensory modalities. Aging is associated with a variety of motor and autonomic symptoms that might be attributed, in part, to impaired spinal cord function. We found that cholinergic neurochemistry is diminished in the spinal cord of 22-24-month-old rats compared with 3-month-old rats. Choline acetyltransferase, high-affinity choline transport and hemicholinium-3 binding to the choline carrier were reduced in the aged spinal cord. The activity of the choline transporter and the hemicholinium-3 binding were decreased in all spinal segments, cervical, thoracic, lumbar and sacral. Hemicholinium-3 binding was reduced in ventral and dorsal horns along all spinal segments. The activity of choline acetyltransferase was decreased only in cervical and lumbar cord. Treatment of aged animals with GM1 induced the recovery of the presynaptic cholinergic markers in the aged spinal cord.

Acetylcholine↗
PubMed1997

Regulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase by dopaminergic drugs.

We provide evidence that dopamine receptors differentially modulate tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the mouse striatum. The dopamine D1 receptor family (D1-like) antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benazepine (SCH 23390), elevated aromatic L-amino acid decarboxylase activity and protein content in striatum, as well as the mRNA for the enzyme in midbrain. The dopamine D1-like receptor agonist, (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF 38393), had no effect on aromatic L-amino acid decarboxylase. The dopamine D1-like drugs had no effect on tyrosine hydroxylase. In contrast, the dopamine D2 receptor family (D2-like) antagonists haloperidol and spiperone elevated both tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities. The increase in aromatic L-amino acid decarboxylase activity was accompanied by elevated enzyme protein content but not mRNA. The dopamine D2-like receptor agonists, bromocriptine, quinpirole and (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT), all decreased striatal tyrosine hydroxylase. Under the conditions used, bromocriptine and 7-OH-DPAT, but not quinpirole, decreased aromatic L-amino acid decarboxylase activity of striatum. Both the dopamine D1- and D2-like receptor antagonists enhanced the turnover of striatal dopamine to differing degrees, as judged by the ratio of acid metabolites of dopamine to dopamine. Taken together our results indicate that aromatic L-amino acid decarboxylase can be modulated independently of tyrosine hydroxylase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

GM1 ganglioside improves spatial learning and memory of aged rats.

GM1 ganglioside, 30 mg/kg, i.p., was administered to cognitively impaired aged rats for 30 days, and spatial learning and memory evaluated in a Morris water maze paradigm. During treatment with GM1, aged animals improved both the acquisition and retention of place navigation, as reflected by reduced escape latencies and swim distances to a hidden platform, and persistently performed better than the aged control animals. Furthermore, the GM1-treated animals showed improved spatial acuity in a spatial probe test when the hidden platform was removed. The improved performance in place navigation was not lost if GM1 treatment was discontinued and the animals tested up to 15 days later. GM1 treatment had no effect on the performance of young rats in the water maze. These results indicate that memory deficits associated with aging can be attenuated by treatment with GM1 ganglioside.

Aging↗
PubMed1997

Cyclic AMP-mediated enhancement of high-affinity choline transport and acetylcholine synthesis in brain.

Intracerebroventricular administration of N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (db-cyclic AMP) to mice increased high-affinity choline transport (HAChT) into synaptosomal preparations from the hippocampus, striatum, and frontal cortex in a time- dose-, and brain region-dependent manner. Similar observations were made when the cyclic AMP analogue 8-bromo-cyclic AMP, the adenylyl cyclase activator forskolin, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine were administered. Inhibition of phosphatase 1 and 2A, with okadaic acid, increased basal choline transport and enhanced the response to db-cyclic AMP. The early increase of HAChT activity induced by db-cyclic AMP was blocked by H-7 and H-89, protein kinase A inhibitors, but not by cycloheximide, a protein synthesis inhibitor. Kinetic analysis of the early changes of HAChT revealed an increase in the apparent Vmax without a change of the Km for choline. Hemicholinium-3 (HC-3) binding was not altered when studied 1 h after db-cyclic AMP administration. In contrast, HC-3 binding and HAChT activity were both elevated when estimated 3 h after the treatment, and pretreatment with cycloheximide partially prevented the db-cyclic AMP-induced HAChT rise. As evidence that enhanced HAChT is associated with a direct action of cyclic AMP-dependent pathways on the cholinergic nerve terminals, addition of 8-bromocyclic AMP to isolated hippocampal synaptosomes induced an increase of HAChT that was prevented by H-89. Choline acetyltransferase activity was not affected at any time during the studies. The synthesis of acetylcholine, however, was enhanced 1 h after db-cyclic AMP addition. Our studies show that cyclic AMP-mimetic compounds appear to modulate the choline carrier by a dual mode: an early increase of the maximal velocity without a change of the number of HC-3 binding sites and a late rise of transport that is accompanied by an increase of HC-3 binding. We postulate that HAChT and consequently acetylcholine synthesis in vivo is modulated, in part, by protein kinase A.

Acetylcholine↗
PubMed1996

Tyrosine hydroxylase and aromatic L-amino acid decarboxylase in mesencephalic cultures after MPP+: the consequences of treatment with GM1 ganglioside.

Rat embryonic mesencephalic cultures were treated with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+), and GM1 ganglioside added after the toxin. Twelve days after a 24-h exposure to MPP+, there was a significant decrement in tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) activities. In addition, TH mRNA was decreased, whereas AAAD mRNA was no different from control cultures. Adding GM1 to control unlesioned cultures had no effect on TH activity or mRNA. In contrast, GM1 modestly increased both the activity and mRNA for AAAD. In the MPP+-treated cultures, GM1 induced a partial recovery of TH and AAAD activity and increased mRNA for both above unlesioned control levels. Our studies demonstrate that GM1 upregulates the synthetic enzymes for dopamine in MPP+-lesioned embryonic mesencephalic cultures, and suggest that TH and AAAD respond differentially to the neurotoxin insult.

1-Methyl-4-phenylpyridinium↗
PubMed1996

Modulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase after inhibiting monoamine oxidase-A.

After acute administration of the monoamine oxidase inhibitor clorgyline there is a reduction of aromatic L-amino acid decarboxylase and tyrosine hydroxylase activity in the mouse striatum. Similar responses were seen after administering the non-selective monoamine oxidase inhibitor pargyline and high, but not low, doses of the selective monoamine oxidase-B inhibitor deprenyl. Changes of tyrosine hydroxylase activity were observed only when subsaturated concentrations of the pteridine cofactor were used for the assay. The monoamine oxidase inhibitors altered the abundance of aromatic L-amino acid decarboxylase and tyrosine hydroxylase mRNA in the midbrain. Pargyline and high doses of deprenyl increased, aromatic L-amino acid decarboxylase mRNA, while clorgyline initially decreased and then increased it. All three compounds caused an early decrease of tyrosine hydroxylase mRNA. The acidic metabolites of dopamine appeared most affected by pargyline and clorgyline, supporting the notion that deamination of striatal dopamine in rodents is primarily by monoamine oxidase-A. Our results suggest, that striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase are apparently modulated via different mechanisms in response to perturbation of dopamine metabolism.

Animals↗
PubMed1996

D2 dopamine receptor antisense increases the activity and mRNA of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in mouse brain.

A D2 dopamine receptor antisense oligodeoxynucleotide was administered intracerebrovetricularly to mice twice on the first day and then once daily for 2 days. The animals were killed 2 h after the last injection, and tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities assayed in the corpus striatum, olfactory tubercle and frontal cortex. Tyrosine hydroxylase activity increased in corpus striatum but not in the olfactory tubercle or in the frontal cortex, while the activity of aromatic L-amino acid decarboxylase increased in all three brain regions. The treatment with the antisense oligomer also elevated the mRNA levels for the two enzymes in the midbrain. In contrast, repeated injection of a vehicle or a random oligomer was without effect on enzyme activity or mRNA D2 antisense oligodeoxynucleotides appear to be selective tools to investigate the role of D2 dopamine receptors in brain.

Animals↗
PubMed1996

Glutamate, glutamine and glutamine synthetase in the neonatal rat brain following hypoxia.

Exposing 7-day-old rat pups to hypoxia, 8% oxygen/92% nitrogen, for 3 h alters glutamate (GLU), glutamine and glutamine synthetase (GS) activity in the striatum, frontal cortex and hippocampus. Immediately following the hypoxic insult there is a rapid transient elevation of GLU followed by a fall and then recovery to control values within 6 h. Glutamine content initially decreased after the termination of the insult, rose thereafter and approached control values within 6 h. GS activity was depressed after hypoxia and gradually returned to normal levels within 6 h. GS mRNA was increased in the three brain regions studied after hypoxia and returned to control values within 24 h. These results suggest that hypoxia alters GLU metabolism in the immature brain.

Animals↗
PubMed1996

Protein kinase C activators decrease dopamine uptake into striatal synaptosomes.

Incubation with either of the protein kinase C activators phorbol 12-myristate 13-acetate (PMA) and sn-1,2 dioctanoylglycerol (DiC8) decreased the uptake of dopamine into striatal synaptosomes, whereas the inactive phorbol ester 4 alpha-PMA had no effect. Washout of PMA and DiC8 failed to reverse the decrease in uptake. Kinetic analysis showed a decrease in the apparent V(max) for the transporter without changes in the K(m). Neither PMA nor DiC8 affected mazindol binding to the dopamine transporter. Preincubation with the protein kinase inhibitor staurosporine prevented the DiC8-induced decrease of dopamine uptake. Furthermore, the protein phosphatase inhibitor okadaic acid decreased dopamine uptake by itself and enhanced the DiC8-induced reduction of uptake. These findings support a role for protein kinase C in modulating dopamine transporter activity.

Animals↗
PubMed1995

Dizocilpine enhances striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity.

Dizocilpine administration enhances dopamine metabolism in the rat striatum, nucleus accumbens, olfactory tubercle, and prefrontal cortex. Concomitant with increased metabolism is enhanced tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities in the striatum and increased mRNA for the two enzymes in the midbrain. Activation of dopaminergic neurons may, in part, explain increased locomotor activity in normal animals and the ability of dizocilpine to potentiate the antiparkinsonian action of L-3,4-dihydroxyphenylalanine in an animal model.

Analysis of Variance↗
PubMed1995

Systemic administration of GM1 ganglioside increases choline acetyltransferase activity in the brain of aged rats.

In the brain of aged rats (22-24 months old) choline acetyltransferase (ChAT) activity in striatum and frontal cortex is lower than in young rats (4-5 months old). In contrast, ChAT activity in the hippocampus is similar in the two groups. Treating old animals with GM1 ganglioside, 30 mg/kg ip, for 30 or 45 days enhances ChAT activity in the striatum and frontal cortex, but has no effect on activity in the hippocampus. ChAT activity remains elevated in the striatum and frontal cortex for 15 days after discontinuing treatment with GM1.

Aging↗
PubMed1995

Aromatic L-amino acid decarboxylase modulation and Parkinson's disease.

Aromatic L-amino acid decarboxylase (AAAD) is the second enzyme in the sequence leading to the synthesis of the catecholamines and serotonin, and it is the rate-limiting enzyme for the synthesis of the trace amines. In the striatum AAAD activity is increased by neuronal firing and diminished or enhanced by activation or blocking dopamine (DA) D1 or D2 receptors, respectively. At least two biochemical mechanisms appear responsible for modulation, short-term involving second messengers and possible phosphorylation, and long-term involving protein synthesis. In Parkinson's disease AAAD is the rate-controlling enzyme for the synthesis of DA when L-DOPA is administered and any change of AAAD activity could have clinical consequences. Indeed, the "on-off phenomenon" where there are fluctuations between off-periods of marked akinesia over several hours with on-periods of improved motility may be related to oscillating or poorly modulated AAAD activity and conversion of L-DOPA to DA. Studies are presented demonstrating how AAAD activity can be enhanced in an animal model of Parkinson's disease and how rapid fluctuations of AAAD can be provoked via second messenger system activation.

Animals↗
PubMed1995

Preproenkephalin mRNA and methionine-enkephalin content are increased in mouse striatum after treatment with nicotine.

A single dose of nicotine increased methionine-enkephalin (Met-Enk) immunoreactivity in the striatum of mice in a time-dependent manner. Met-Enk content reached maximum by approximately 1 h after nicotine and returned to control values by 6 h. The response to nicotine was blocked by pretreating animals with the nicotinic receptor antagonist mecamylamine. In contrast, pretreating mice with the muscarinic receptor antagonist atropine or the dopamine receptor antagonist haloperidol did not block the response. A single dose of nicotine also increased mRNA for the precursor peptide preproenkephalin (PPE). The increase of PPE mRNA preceded that of Met-Enk and reached a maximum by approximately 30 min after nicotine. PPE mRNA levels returned to near normal by approximately 3 h and increased again by 6 h after nicotine. Daily administration of nicotine for 14 days increased Met-Enk content and PPE mRNA in the striatum of mice as well. Taken together, our results suggest that nicotinic receptors modulate Met-Enk content and PPE mRNA in the mouse striatum.

Animals↗
PubMed1994

GM1 ganglioside and darkly staining neurons in brains of rats subjected to neonatal hypoxia-ischemia.

Rat pups, seven days old, with right carotid artery ligations were exposed to an atmosphere of oxygen 8% remainder nitrogen for 2 hr. The animals that survived for three weeks after the hypoxic-ischemic episode had clusters of darkly stained (hematoxylin-eosin) neurons in the cortex and reduced uptake of dopamine (frontal cortex) and choline (frontal cortex, hippocampus and striatum) in preparations of synaptosomes. Treatment with GM1 ganglioside partially corrected the loss of uptake activity and increased the number of darkly stained neurons.

Animals↗
PubMed1994

Phorbol ester administration transiently increases aromatic L-amino acid decarboxylase activity of the mouse striatum and midbrain.

Aromatic L-amino acid decarboxylase (AAAD) is required for the synthesis of catecholamines, serotonin, and the trace amines. We found that the protein kinase C activator phorbol 12-myristate 13-acetate administered intracerebroventricularly transiently increased AAAD activity by 30-50% over control values within approximately 30 min in the striatum and midbrain of the mouse. The enzyme increase was manifested as an apparent increase of Vmax with little change of Km for either L-3,4-dihydroxyphenylalanine or pyridoxal phosphate. Chelerythrine, a protein kinase C inhibitor, prevented the phorbol ester-induced increase of AAAD. Moreover, okadaic acid, a serine/threonine-selective protein phosphatase 1 and 2A inhibitor, also increased AAAD activity in the mouse striatum and midbrain. Taken together, these observations suggest that protein kinase C-mediated pathways modulate AAAD activity in vivo.

Alkaloids↗
PubMed1994

Enhanced MPTP neurotoxicity after treatment with isoflurophate or cholinergic agonists.

Administration of the irreversible cholinesterase inhibitor isoflurophate (diisopropylfluorophosphate, DFP) before 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhanced the loss in tyrosine hydroxylase activity and dopamine and 3,4-dihydroxy-phenylacetic acid content in the striatum of mice in a dose-dependent manner. The effect of DFP on the MPTP-induced changes of dopaminergic markers was evident 30 days after initiating treatment, suggesting augmented neurotoxicity. Neurotoxicity was also enhanced by prior treatment with nicotine, carbachol or oxotremorine. We conclude that activation of either muscarinic or nicotinic receptors enhances the neurotoxicity of MPTP.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Neonatal hypoxia: early neurotransmitter responses and the consequences of treatment with GM1 ganglioside.

Brain neurotransmitter content and uptake activity were assessed in the brains of 7-day-old rats 15 min after exposure to hypoxia (8% O2-92% N2) for 3 hr. Glutamate, dopamine and choline uptake were decreased in the striatum, hippocampus and frontal cortex of the hypoxic animals. Moreover, the content of glutamate, dopamine and serotonin as well as the acidic metabolites of the two biogenic amines increased in the same tissues. Acetylcholine content was decreased in all three brain regions as well. Treating the animals with GM1 ganglioside before the insult prevented all neurochemical changes in the hypoxic neonatal brain. GM1 also prevented an hypoxia-induced decrease in phorbol ester binding. Finally, GM1 ganglioside reduced the mortality rate resulting from the hypoxic insult. Our results along with those in the literature suggest that GM1 might be useful for combating the pathology associated with perinatal hypoxia.

Animals↗