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Biomedical subjects

N H Neff

Publications and source records attributed to N H Neff.

At least 73 records · Page 4Linked to original sources
PubMed1989

Treatment with GM1 ganglioside reverses dopamine D-2 receptor supersensitivity induced by the neurotoxin MPTP.

Treatment of mice with the neurotoxin MPTP to destroy nigrostriatal dopaminergic neurons results in up-regulation of D-2 receptors in the striatum when studied after 30 days. Administration of GM1 ganglioside after inducing the lesion prevents D-2 receptor up-regulation. The ganglioside has no apparent effect when administered to normal animals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

GM1 ganglioside-induced recovery of nigrostriatal dopaminergic neurons after MPTP: an immunohistochemical study.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice results in the loss of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the mouse striatum and a loss of cells containing tyrosine hydroxylase (TH)-immunoreactivity from the substantia nigra. The cells that remained in the nigra after MPTP treatment were smaller in diameter than normal cells. Treatment with GM1 ganglioside beginning 24 h after establishing the MPTP lesion resulted in partial restoration of DA and DOPAC content in the striatum and an increase in the diameter of the TH-immunoreactive nigra cells. It appears, therefore, that treatment of MPTP-intoxicated mice with GM1 ganglioside results in the partial restoration of both the biochemistry and morphology of dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Angiotensin II stimulates phosphoinositide turnover in the rat myometrium.

Angiotensin II (AII) activates rat myometrium phospholipase C resulting in the hydrolysis of phosphoinositides. The response to AII is concentration- and time-dependent, and it is blocked by saralasin. During pregnancy there is a loss of responsiveness to AII at the site of placental implantation that appears to return during parturition.

Angiotensin II↗
PubMed1989

Continued administration of GM1 ganglioside is required to maintain recovery from neuroleptic-induced sensorimotor deficits in MPTP-treated mice.

Injection of a dose of haloperidol that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. Chronic GM1 ganglioside administration improves the behavioral impairments, partially restores striatal dopamine (DA) content and prevents DA D-2 receptor up-regulation. Discontinuation of GM1 ganglioside treatment results in a time-dependent decline of striatal DA content to pretreatment pathological levels, return of haloperidol-induced sensorimotor deficits and a rise of DA D-2 receptor density in the striatum. Apparently, continuous administration of GM1 ganglioside is necessary to maintain the biochemical and behavioral recovery in the MPTP-treated mouse. These observations may provide useful cues for understanding the mechanism of action of GM1 ganglioside.

Animals↗
PubMed1989

Gestational alterations in phospholipase C coupled muscarinic response.

In the pregnant rat, carbachol-induced phosphoinositol hydrolysis by myometrium at the placental attachment region progressively decreased toward term, whereas hydrolysis was relatively stable in the myometrium of the non-attachment region. Tritium-quinuclidinyl benzilate binding increased in the myometrium of non-attachment regions as pregnancy progressed. At placental attachment sites binding remained relatively stable until parturition when it increased. Apparently the myometrium associated with the placental attachment site is less sensitive to cholinergic influence during pregnancy compared with the non-attachment site when evaluated by muscarinic activation of phospholipase C or ligand binding.

Animals↗
PubMed1989

Modulation of retinal aromatic L-amino acid decarboxylase via alpha 2 adrenoceptors.

Aromatic L-amino acid decarboxylase (AAAD) activity of the rat retina increases when animals are placed in a lighted environment from the dark. The rise of activity can be inhibited by administering alpha 2 adrenoceptor agonists. In the dark, the enzyme activity can be made to increase by administering alpha 2 adrenoceptor antagonist drugs. Kinetic analysis indicates that the maximum velocity of the enzyme increases with little change of the Km for the substrate L-3,4-dihydroxyphenylalanine or the cofactor pyridoxal-5'-phosphate. The rise of activity in the light and in the dark after alpha 2 antagonists can be blocked by administering cycloheximide, suggesting that protein synthesis is needed for the response. We speculate that epinephrine released in the dark from a subpopulation of retinal amacrine cells onto alpha 2 receptors suppresses AAAD activity that is associated with dopaminergic amacrines.

Animals↗
PubMed1989

Pharmacological characterization of rat retinal dopamine receptors.

The dopamine (DA) D-1 and D-2 receptors coupled to adenylate cyclase in the rat retina were characterized pharmacologically. In confirmation of reports using other neural tissues, activation of D-1 receptors with DA, apomorphine or SKF 38393 resulted in activation of adenylate cyclase and enhanced accumulation of cyclic AMP (cAMP). The response to DA was blocked by SCH 23390, a D-1 receptor antagonist. D-2 receptors negatively coupled to adenylate cyclase were demonstrated by preincubating retina with SCH 23390 and then with DA or apomorphine. D-2 receptor responses were also elicited with quinpirole or bromocriptine, D-2 receptor agonists, in the absence of SCH 23390. (+)-Butaclamol, but not (-)-butaclamol, blocked the D-2 receptor-induced decrease of cAMP. Moreover, I-sulpiride was more active than d-sulpiride in reversing the DA-induced inhibition of cAMP accumulation. D-1 and D-2 receptor responses were also evident in forskolin-activated retina. The intraocular injection of pertussis toxin prevented the fall of cAMP and enhanced the rise of cAMP by DA, indirectly implicating the need for a guanine nucleotide regulatory protein in the process. Our results demonstrate that retinal tissue contains DA receptors that are similar to those found in brain and they imply that therapeutic agents that interact with the receptors in brain might interact with the receptors in retina.

Adenylyl Cyclases↗
PubMed1989

Pharmacological characterization of the muscarinic receptors mediating phosphoinositide hydrolysis in rat myometrium.

Activation of rat uterine myometrial muscarinic receptors with a variety of agonists results in increased phosphatidylinositol metabolism. Activation with carbachol is concentration- and time-dependent and is most apparent by following the accumulation of inositol monophosphate although there are small but significant increases of inositol bisphosphate and inositol trisphosphate. Carbachol stimulation of phospholipid turnover is greatest in the upper third of the uterus. The carbachol-induced increase of inositol monophosphate is antagonized by atropine and by the selective M-3 muscarinic receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide. Pirenzepine, a selective M-1 receptor antagonist is less active, whereas gallamine and 11-2[[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, selective M-2 receptor antagonists, are minimally effective suggesting that muscarinic M-3 receptors modulate phospholipid turnover in the rat myometrium. Displacement of tritium-quinuclidinyl benzilate binding by muscarinic antagonists also supports the presence of M-3 receptors in the uterus. Incubation with phorbol 12, 13-dibutyrate significantly reduced the accumulation of inositol monophosphate induced by carbachol implying that protein kinase C might modulate the responsiveness of the M-3 receptors in the rat uterus. Our results suggest that the intracellular concentration of calcium required for the contraction of the rat myometrium may be modulated, in part, through M-3 muscarinic receptors coupled to phospholipase C-activated turnover of phosphoinositides.

Animals↗
PubMed1988

Administration of GM1 ganglioside eliminates neuroleptic-induced sensorimotor deficits in MPTP-treated mice.

Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. GM1 ganglioside treatment eliminates all of these behavioral impairments and also partially restores striatal dopamine content. These observations suggest that the MPTP-treated mouse may be a valuable model for studying mechanisms underlying parkinsonism and that administration of GM1 ganglioside may be an effective therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

MPP+ depletes retinal dopamine and induces D-1 receptor supersensitivity.

Intraocular administration of 1-methyl-4-phenylpyridinium ion (MPP+) to mice resulted in a dose-dependent depletion of retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid. Pretreatment with benztropine partially prevented the MPP+-induced depletion. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was less active than MPP+ for depleting DA when administered by the same route and pretreatment with deprenyl partially prevented the depletion. Supersensitivity of retinal D-1 receptors resulted following MPP+-induced DA depletion.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Aromatic L-amino acid decarboxylase activity of the rat retina is modulated in vivo by environmental light.

Aromatic L-amino acid decarboxylase (AAAD) activity of rat retina is low in animals placed in the dark. When the room lights are turned on, activity rises for almost 3 h and reaches values that are about twice the values found in the dark. A study of the kinetics of the enzyme revealed that the apparent Km values for L-3,4-dihydroxyphenylalanine and pyridoxal-5'-phosphate were unchanged in light- and dark-exposed animals, whereas the Vmax increased in the light. Treating the animals with cycloheximide before exposure to light prevented the increase of enzyme activity. Immunotitration with antibodies to AAAD suggested that more enzyme molecules are present in the light than in the dark. When the room lights are turned off AAAD activity drops rapidly at first and then more slowly, suggesting that at least two processes are responsible for the fall of enzyme activity. Exposure to short periods of dark followed by light results in a rapid increase of AAAD activity. Mixing homogenates from light- and dark-exposed rats results in activity values that are less than expected, suggesting the presence of an endogenous inhibitor(s). These studies demonstrate that AAAD activity is modulated in vivo.

Animals↗
PubMed1988

Treatment with GM1 ganglioside restores striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 30 mg/kg i.p. daily for 7 days, was administered to mice. This dosage regimen resulted in an approximately 50% reduction of striatal dopamine (DA) level. Chronic administration of GM1 ganglioside (II3NeuAc-GgOse Cer), beginning between 1 to 4 days after terminating MPTP dosing, resulted in partial restoration of the striatal DA level. From dose- and time-response studies, it appeared that 30 mg/kg i.p. of GM1 administered daily for approximately 23 days resulted in an approximately 80% restoration of the DA level and complete restoration of the 3,4-dihydroxyphenylacetic acid (DOPAC) content. This dosage of GM1 also restored the turnover rate of DA in the striatum to near normal. Discontinuing GM1 treatment resulted in a fall of DA and DOPAC levels to values found in mice treated with MPTP alone. There was no evidence for regeneration of nerve terminal amine reuptake in the GM1-treated mice as evaluated by DA uptake into synaptosomes. Our biochemical findings in animals suggest that early GM1 ganglioside treatment of individuals with degenerative diseases of dopaminergic nigrostriatal neurons might be fruitful.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Pharmacological characterization of muscarinic receptors mediating inhibition of adenylate cyclase activity in the rat retina.

Incubation of the rat retina with acetylcholine resulted in about a 20 to 30% decrease of basal cyclic AMP accumulation. Oxotremorine, arecoline, [4-hydroxy-2-butynyl]trimethylammonium chloride, m-chlorocarbanilate and carbachol also inhibited cyclic AMP accumulation. Nicotine had no effect. The response was blocked by atropine and pirenzepine but not gallamine. Intraocular injection of pertussis toxin 72 hr before testing also blocked the response to acetylcholine. The presence of forskolin exaggerated the response to acetylcholine. Intraocular injection of the cholinotoxin AF64A resulted in apparent supersensitivity of the response to acetylcholine. Our results suggest that rat retina contains muscarinic M1 receptors that are coupled negatively to adenylate cyclase.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1988

Muscarinic receptor-mediated phosphoinositide hydrolysis in the rat retina.

In this report, muscarinic receptor-mediated phosphoinositide (PI) hydrolysis is characterized pharmacologically in the rat retina. In the presence of eserine, acetylcholine (ACh) elicited a concentration-dependent increase in inositol monophosphate with a calculated EC50 of about 2.8 microM. Maximum increase was achieved with about 100 microM ACh. Cholinergic receptor agonists stimulated phospholipase C-mediated hydrolysis of PI with the following rank order of potency: ACh = oxotremorine greater than McN-A-343 greater than bethanechol greater than arecoline = carbachol greater than muscarine. Oxotremorine analogs stimulated PI hydrolysis with the following rank order of potency: ACh = oxotremorine = oxotremorine-2 greater than oxotremorine-M = oxotremorine-4. Carbachol-mediated Pl hydrolysis was blocked by atropine and by the putatively selective muscarinic type 1 (M1) receptor antagonist, pirenzepine, with apparent Ki values of 0.1 and 1.0 nM, respectively. In contrast, the selective muscarinic type 2 (M2) antagonists, gallamine and AF-DX 116, failed to inhibit the action of carbachol. These findings demonstrate that stimulation of muscarinic receptors in the rat retina leads to PI hydrolysis and that these receptors appear to be M1 cholinergic receptors.

Adenylyl Cyclases↗
PubMed1987

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) accelerates the accumulation of lipofuscin in mouse adrenal gland.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes degeneration of nigrostriatal dopaminergic neurons. Recently, we reported that it also destroys dopaminergic neurons in retina and it induces the accumulation of lipofuscin. We now present morphologic and biochemical evidence that MPTP causes the accumulation of lipofuscin in the adrenal cortex. We speculate, that generation of free radicals during the transformation of MPTP to metabolites might be responsible for lipofuscin formation. MPTP-induced accumulation of lipofuscin may be a useful model for studying the biochemistry of the aging process.

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