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N H Neff

Publications and source records attributed to N H Neff.

At least 55 records · Page 3Linked to original sources
PubMed1993

Distribution of aromatic L-amino acid decarboxylase mRNA in mouse brain by in situ hybridization histology.

Aromatic L-amino acid decarboxylase (AAAD) is the second enzyme in the sequence leading to the synthesis of catecholamines or serotonin. Antisense riboprobes for aromatic L-amino acid decarboxylase mRNA were used to map the gene in mouse brain by in situ hybridization. The substantia nigra, the ventral tegmental nucleus, the dorsal raphe nucleus, the locus coeruleus, and the olfactory bulb contained the highest signal for AAAD mRNA. After treatment with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the signal disappeared in the substantia nigra, decreased somewhat in the ventral tegmental area, and remained unchanged in the dorsal raphe nucleus. Hypothalamic and cerebellar Purkinje neurons known to contain histidine decarboxylase or glutamic acid decarboxylase, respectively, were unlabeled by the probes. However, neurons in the deep layers of the frontal cortex, many thalamic nuclei, and the pyramidal neurons of the hippocampus were lightly to moderately labeled for mouse AAAD mRNA. The presence of AAAD message in these neurons suggests that the enzyme has functions other than that for the synthesis of the classical biogenic amine neurotransmitters.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Aromatic L-amino acid decarboxylase activity of mouse striatum is modulated via dopamine receptors.

Aromatic L-amino acid decarboxylase (AAAD) activity is enhanced in the striatum of control and MPTP-treated mice after administration of a single dose of the dopamine receptor antagonists haloperidol, sulpiride, and SCH 23390. MPTP-treated mice appear more sensitive to the antagonists, i.e., respond earlier and to lower doses of antagonists than control mice. The rise of AAAD activity induced by the antagonists is prevented by pretreatment with cycloheximide. The apparent Km values for L-3,4-dihydroxyphenylalanine (L-DOPA) and pyridoxal 5-phosphate appear unchanged after treatment with the antagonists. Increased AAAD activity was observed also after subchronic administration of dopamine receptor antagonists or treatment with reserpine. A single dose of a selective dopamine receptor agonists had no effect on AAAD activity. In contrast, administration of L-DOPA, quinpirole, or SKF 23390 for 7 days lowers AAAD activity in the striatum. We conclude that AAAD is modulated in striatum via dopaminergic receptors.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Evidence for cyclic AMP-mediated increase of aromatic L-amino acid decarboxylase activity in the striatum and midbrain.

Aromatic L-amino acid decarboxylase (AAAD) activity of mouse striatum and midbrain increased after an intracerebroventricular injection of either forskolin or 8-bromo-cyclic AMP. The increase was transient, peaking between 15 and 30 min and returning to baseline by approximately 90 min. The increase of AAAD activity after forskolin was not affected by pretreatment with cycloheximide. Kinetic studies indicated an apparent increase of Vmax with little change of the Km for L-DOPA or pyridoxal 5'-phosphate. We conclude that AAAD activity of striatum and midbrain can be modulated by a cyclic AMP-dependent process.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

GM1 ganglioside improves dopaminergic markers of rat mesencephalic cultures treated with MPP+.

Rat embryonic mesencephalic cultures were employed to evaluate the consequences of adding GM1 ganglioside to cultures lesioned with the selective neurotoxin 1-methyl-4-phenylpyridinium (MPP+). MPP+ reduced dopamine and DOPAC content, dopamine uptake, aromatic L-amino acid decarboxylase activity, and the number of tyrosine hydroxylase-immunopositive neurons. The immunopositive neurons that remained were aberrant. All of these parameters were partially restored by adding GM1 ganglioside to the cultures. The response to GM1 was not altered by prior treatment of the cultures with cytosine beta-D-arabinofuranoside to reduce the number of glial cells. Dopamine uptake activity restored by GM1 was lost if GM1 was removed from the culture.

1-Methyl-4-phenylpyridinium↗
PubMed1992

c-fos mRNA in mouse brain after MPTP treatment.

The neurotoxin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a transient increase of mRNA for the immediate-early gene c-fos in the mouse brain. The c-fos mRNA level is MPTP dose-dependent and is evident in all brain regions tested including striatum, hypothalamus, cortex, hippocampus, cerebellum and midbrain. There are regional differences in the time-course for the rise of c-fos mRNA. Pretreatment with deprenyl, a selective monoamine oxidase B inhibitor, pargyline, a nonselective monoamine oxidase inhibitor, or mazindol, a dopamine uptake transport inhibitor, does not prevent the c-fos mRNA increase, suggesting that the elevation is due to the action of MPTP and not its neurotoxic metabolite MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Expression of cloned aromatic L-amino acid decarboxylase in Xenopus laevis oocytes.

Sense mRNA coding for bovine adrenal medulla aromatic L-amino acid decarboxylase (AADC) was expressed following microinjection into Xenopus laevis oocytes. The expressed enzyme activity was stereoselective for L-5-hydroxytryptophan and L-DOPA and blocked by NSD-1015 an inhibitor of AADC. Heating the expressed enzyme at 55 degrees C resulted in a parallel loss of activity towards both substrates. Our findings are consistent with the prevailing notion that a single enzyme is able to decarboxylate both substrates in vivo.

Adrenal Glands↗
PubMed1992

GM1 ganglioside enhances cholinergic parameters in the brain of senescent rats.

GM1 ganglioside and nerve growth factor both promote the recovery of injured central cholinergic neurons in young animals. Brain cholinergic activity declines with aging and nerve growth factor has been shown to correct cholinergic deficits in senescent animals. We have administered GM1, to young (three months old) or senescent (22-24 months old) rats and evaluated acetylcholine and choline content, choline acetyltransferase and acetylcholinesterase activity as well as choline uptake in striatum, hippocampus and frontal cortex. For some studies, nerve growth factor was administered alone or together with GM1. Our results indicate that cholinergic neurochemical parameters are decreased in some brain areas of senescent animals and that both GM1 and nerve growth factor can enhance their recovery.

Acetylcholine↗
PubMed1991

Differential changes of retina dopamine binding sites and adenylyl cyclase responses following 6-hydroxydopamine treatment.

Both dopamine D1 and D2 receptors are present in rat retina. D1 receptors are positively coupled to adenylyl cyclase, while D2 receptors are negatively coupled. After intraocular administration of the neurotoxin 6-hydroxydopamine (6-OHDA) there is depletion of retinal dopamine by about 90%, as well as a decrease of the number of D1 and D2 receptor binding sites. Following the 6-OHDA lesion, there is an enhancement of the D1 receptor-stimulated accumulation of cyclic-AMP and a loss of D2 receptor-inhibited accumulation of cyclic-AMP. Our results suggest that some of the retinal D2 receptors are coupled to adenylyl cyclase and some are not.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Modulation of muscarinic receptor-mediated adenylate cyclase and phospholipase C responses in rat retina.

1. Agonist activation of rat retina muscarinic receptors results in suppression of cyclic AMP (cAMP) generation and enhanced phosphoinositide hydrolysis. 2. Pharmacological manipulations that elevate cAMP or stable analogues of cAMP attenuate the acetylcholine (ACh)-induced enhancement of phosphoinositide hydrolysis. We postulate that cross-talk between adenylate cyclase and phospholipase C signal transducing systems probably exists in rat retina, as has been described for other systems. 3. Intraocular administration of pertussis toxin attenuated the response of both adenylate cyclase and phospholipase C to muscarinic stimulation, suggesting that some retinal muscarinic receptors are apparently coupled to their effector systems via pertussis toxin sensitive G proteins.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Preproenkephalin mRNA and methionine-enkephalin increase in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment.

Dopaminergic neurons that project to the striatum from the substantia nigra are thought to modulate methionine-enkephalin (Met-Enk) metabolism in the striatum. We administered a dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that produces a moderate depletion of dopamine in striatum, about 50%, without overt motor deficits, and found that Met-Enk-like immunoreactivity and preproenkephalin mRNA content increased in the tissue. Pretreatment with the monoamine oxidase B inhibitor deprenyl or the dopamine transport blocker nomifensine prevented these changes, suggesting that the changes were related to the partial loss of dopaminergic neurons rather than to MPTP. Moreover, administering GM1 ganglioside, which partially restores the MPTP-induced dopaminergic deficit, partially corrected the Met-Enk changes in the striatum as well. These findings are consistent with the hypothesis that dopaminergic input to the striatum, in part, modulates Met-Enk metabolism. Moreover, they show that moderate nigrostriatal lesions are sufficient to elevate Met-Enk and preproenkephalin mRNA contents and that restoration of dopaminergic function, as in our studies with GM1 ganglioside, restores the content of Met-Enk.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Epidermal growth factor enhances striatal dopaminergic parameters in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse.

Intracerebroventricular infusion of epidermal growth factor (EGF) into mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic nigrostriatal neurons partially enhanced the content of dopamine (DA) and 3,4-dihydroxyphenylacetic acid as well as the activity of tyrosine hydroxylase in the striatum. EGF also enhanced these parameters in control, unlesioned animals. Neurotrophic activity also was observed in embryonic mesencephalic cultures, where EGF enhanced DA uptake after a lesion with the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium ion. Our in vivo and in vitro studies suggest that EGF may be a neurotrophic factor for dopaminergic neurons, or may act indirectly by inducing the release of a dopaminergic trophic factor from other cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Modulation of dopamine metabolism in the retina via dopamine D2 receptors.

When rats are placed in a lighted environment from the dark retinal DOPAC increases. There is no significant change of retinal dopamine (DA) under either lighting condition. Blockade of aromatic L-amino acid decarboxylase results in a more rapid accumulation of DOPA in the retina of animals in the light than in the dark implying that DA synthesis and metabolism are more rapid in the light than in the dark. Retinal DOPAC increases in the dark and in the light when rats are treated with the DA D2 antagonists sulpiride and spiperone. Treatment with the D2 agonist, quinpirole, lowers the content of DA in the retina of rats kept in the dark or exposed to light. D1 receptor drugs induce only limited changes in DA metabolism. We conclude that D2 receptors play a principal role for modulating DA synthesis and metabolism in the rat retina.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Differential recovery of dopamine synthetic enzymes following MPTP and the consequences of GM1 ganglioside treatment.

After 7 days of treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 30 mg/kg i.p., tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) activities are decreased by more than 50% in the mouse striatum. Within 30 days, AAAD activity returns while TH activity remains depressed. TH activity can be restored to near normal by chronic treatment with GM1 ganglioside, 30 mg/kg i.p.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Dopamine receptor plasticity following MPTP-induced nigrostriatal lesions in the mouse.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) destroys dopamine-containing nigrostriatal neurons and increases the apparent Bmax of both D1 and D2 binding sites in the striatum. However, the changes of Bmax occur at different intervals after the lesion. Up-regulation of D2 sites becomes evident about 3 weeks after the lesion and lasts for about 3 months. In contrast, about 3 months are required for the up-regulation of D1 sites and increased binding is still evident after 5 months.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Ethylcholine aziridinium ion depletes acetylcholine and causes muscarinic receptor supersensitivity in rat retina.

Three weeks after a single intravitreal injection of ethylcholine aziridinium ion (AF64A), there was a significant depletion of retinal acetylcholine (ACh) content. The depletion was accompanied by an increase of [3H]quinuclidinyl benzilate binding sites and a greater than control conversion of myo-[3H]inositol to inositol monophosphate following incubation with ACh. These changes are consistent with receptor supersensitivity due to AF64A-induced denervation.

Acetylcholine↗
PubMed1990

Aromatic L-amino acid decarboxylase is modulated by D1 dopamine receptors in rat retina.

Aromatic L-amino acid decarboxylase (AAAD) activity of rat retina increases when animals are placed in a lighted environment from the dark. The increase of activity can be inhibited by administering the selective dopamine D1 receptor agonist SKF 38393, but not the selective D2 agonist quinpirole, or apomorphine. Conversely, in the dark, enzyme activity can be enhanced by administering the selective D1 antagonist SCH 23390 or haloperidol, but not the selective D2 antagonist (-)-sulpiride. Furthermore, in animals exposed to room light for 3 h, the D1 agonist SKF 38393 reduced retinal AAAD activity, and this effect was prevented by prior administration of SCH 23390. In contrast, quinpirole had little or no effect when administered to animals in the light. Kinetic analysis indicated that the apparent Vmax for the enzyme increases with little change in the apparent Km for the substrate 3,4-dihydroxyphenylalanine or the cofactor pyridoxal-5'-phosphate. We suggest that dopamine released in the dark tonically occupies D1 receptors and suppresses AAAD activity. When the room light is turned on, D1 receptors are vacated and selective D1 agonists can either prevent the rise of AAAD or reverse light-enhanced AAAD activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Hypoxia-induced neurotransmitter deficits in neonatal rats are partially corrected by exogenous GM1 ganglioside.

Exposure of 7-day-old rats to 7% oxygen/balance nitrogen for 2 h results in selective changes of cholinergic, serotonergic, and dopaminergic neuronal markers in the frontal cortex, hippocampus, and striatum when evaluated 3 weeks after the insult. There is also about a 15% deficiency in brain weight. Treatment with GM1 ganglioside, 50 mg/kg i.p., for 2 days before and for 3 weeks after the hypoxic insult partially corrects the neurodevelopmental abnormalities including the deficiency in brain weight. We conclude that GM1 ganglioside might have therapeutic potential for treating suspected neonatal hypoxia.

3,4-Dihydroxyphenylacetic Acid↗