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Biomedical subjects

C Bakhit

Publications and source records attributed to C Bakhit.

14 recordsLinked to original sources
PubMed1992

Recovery of cholinergic phenotype in the injured rat neostriatum: roles for endogenous and exogenous nerve growth factor.

Polyclonal antibodies against recombinant human nerve growth factor (rhNGF) potently inhibited PC12 neurite outgrowth, blocked high-affinity 125I-rhNGF binding but not its receptor, and cross-reacted with rat, mouse, and human nerve growth factor (NGF) but not with brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, insulin-like growth factor, epidermal growth factor, or activin A. Immunocytochemistry revealed many NGF-positive neurons in the rat neostriatum. The NGF-positive neurons disappeared by 3 days after mechanical injury to the neostriatum and were replaced by intensely NGF- and glial fibrillary acidic protein-positive astrocytes. Enzyme-linked immunosorbent assay measurements revealed that the NGF content of the injured striatum was elevated by eightfold 3 days postinjury and by twofold 2 weeks later. The high-affinity choline uptake (HACU) into cholinergic nerve terminals was decreased by 23% at 2 and 4 weeks postinjury, yet choline acetyltransferase (ChAT) activity in these neurons was unchanged at 2 weeks and decreased by 14% at 4 weeks. Daily infusion of 1 microgram of rhNGF into the injury area did not alter the loss of HACU. However, this treatment elevated ChAT activity by 23-29% above intact neostriatal levels and by 53-65% relative to HACU at both survival times. Thus, lesion-induced increases in NGF levels within astrocytes are associated with maintenance of striatal ChAT activity at normal levels following cholinergic injury, even with decreases in HACU. Pharmacologic doses of rhNGF can further augment ChAT activity in damaged cholinergic neurons, showing the usefulness of exogenous NGF even when endogenous NGF is elevated in response to injury.

Animals↗
PubMed1991

Increase in glia-derived nerve growth factor following destruction of hippocampal neurons.

It is currently believed that under normal conditions hippocampal neurons synthesize nerve growth factor (NGF) which may provide trophic support for cholinergic neurons projecting from the basal forebrain. The concept that glial cells are mobilized to increase the production of NGF following destruction of hippocampal neurons was examined. Excitotoxin-induced destruction of the dorsal hippocampal neurons resulted in a massive and prolonged increase in NGF-like immunoreactivity (LI). Immunostaining for NGF-LI and the glial marker, glial fibrillary acidic protein (GFAP), revealed that the source of increased NGF-LI production following the lesion were reactive astrocytes. Thus, glial cells assume the role of providing trophic support following loss of target neurons.

Animals↗
PubMed1991

Increase in nerve growth factor-like immunoreactivity and decrease in choline acetyltransferase following contusive spinal cord injury.

We have previously described a graded spinal cord injury model in the rat. Mild contusive injury results in an initially severe functional deficit that is attenuated over time to reveal the mild chronic deficits that characterize this injury. In this study, we have shown that mild contusive injury also results in a significant decrease in choline acetyltransferase (ChAT) activity during the first week after injury. At 1 week ChAT activity is maximally reduced at the site of the contusion and is also significantly lowered throughout the spinal cord. ChAT activity then rebounds during the following 3 weeks, partially at the injury site where there is considerable loss of gray and white matter, and completely in rostral and caudal cord segments. The rebound in ChAT activity is temporally associated with the partial recovery of function. Further, the changes in ChAT activity after injury are mirrored by changes in nerve growth factor-like immunoreactivity (NGF-LI) as determined by a specific two-site ELISA. NGF-LI increases significantly after injury, reaching a maximum at 7 days after contusion and at the injury site. However, levels of NGF-LI are also significantly increased throughout the spinal cord. NGF-LI then decreases at 2 and 4 weeks as ChAT activity rebounds. Further experiments will be needed to examine the possibility of a role for NGF in promoting the recovery of function after spinal cord injury.

Animals↗
PubMed1991

Receptor-mediated transport of human recombinant nerve growth factor from olfactory bulb to forebrain cholinergic nuclei.

Receptors for nerve growth factor are present in the olfactory bulb and in cholinergic nuclei that send projections to the olfactory bulb. The retrograde transport of 125I-labeled recombinant human nerve growth factor (rhNGF) was demonstrated in the rat 18 h following an injection of [125I]rhNGF into the left olfactory bulb. In each of six animals, [125I]rhNGF label was observed in the ipsilateral horizontal limb of the diagonal band and, in four of the 6 animals, in the vertical limb of the diagonal band. Label was not observed in any other brain region except within the injected olfactory bulb. The transport of label to the diagonal band was blocked by the injection of 170-fold greater concentration of unlabeled rhNGF. Emulsion autoradiography of hematoxylin/eosin counterstained sections revealed silver grains clustered over numerous cell profiles that resembled neurons. In contrast, cerebellar injections of [125I]rhNGF, with or without unlabeled rhNGF, did not label diagonal band neurons, nor the lateral vestibular or red nuclei, from which originate the primary cholinergic afferents to cerebellum. The receptor-dependent transport of NGF from olfactory bulb to forebrain cholinergic nuclei suggests that this projection, unlike pontomesencephalic cholinergic pathways, may be responsive to endogenous NGF or exogenously administered rhNGF.

Animals↗
PubMed1991

Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGF-like immunoreactivity.

High-affinity binding sites for recombinant human NGF (rhNGF) were studied in the caudate-putamen of the adult rat and rabbit. Displaceable 125I-rhNGF binding sites were densely distributed throughout the caudate-putamen and were 2-3-fold more prevalant in the ventrolateral and lateral than in the medial caudate-putamen. The amount of nondisplaceable binding did not vary throughout the caudate-putamen. The medial-to-lateral receptor gradient was correlated (r = +0.99) with a 2-3-fold medial-to-lateral increase in ChAT activity. In contrast, NGF-like immunoreactivity (NGF-LI) was prevalent but uniformly distributed in the caudate-putamen. Lesions of intrinsic cholinergic neurons by quinolinic acid produced extensive gliosis in the medial, central, and lateral caudate-putamen, yet 125I-rhNGF binding was decreased in each of these regions. The activity of ChAT and 125I-rhNGF binding throughout the caudate-putamen were each decreased by 40% following quinolinic acid. Binding was not changed after 70-77% dopamine nerve terminal depletions induced by 6-hydroxydopamine, demonstrating a nonglial, nondopaminergic locus for striatal NGF binding sites. The cholinergiclike topography of NGF binding sites throughout the intact caudate-putamen, the parallel decreases of cholinergic neurons and NGF binding sites following intrinsic neuronal loss, and the uniform neostriatal gradient of NGF-LI are consistent with the trophic role of endogenous NGF for cholinergic interneurons of the caudate-putamen.

Animals↗
PubMed1989

The pharmacokinetics and pharmacodynamics of a human relaxin in the mouse pubic symphysis bioassay.

The effects of dose, route, regimen, and the presence or absence of a repository vehicle [benzopurpurine (BPP)] were determined for a human relaxin (hRlx) in the mouse pubic symphysis bioassay. Administration of 88 micrograms/kg hRlx sc in 1% BPP resulted in delayed, prolonged absorption. Although peak hRlx concentrations were lower, serum concentrations remained elevated longer in the presence of BPP compared to a single sc administration of hRlx in saline at the same dose. The bioavailabilities with and without BPP were similar (109 and 96%, respectively). While the pharmacodynamic effect (i.e. lengthening of the pubic ligament in estrogen-primed mice) was approximately maximum at 88 micrograms/kg hRlx sc with BPP, single sc administration of hRlx without BPP up to 264 micrograms/kg had no effect on pubic ligament length. In the absence of the BPP vehicle, manipulation of the regimen (e.g. multiple sc doses) showed that emulation of the serum concentration-time profile observed for hRlx in the presence of BPP resulted in similar pharmacodynamic effects. It appears that BPP delays the absorption of hRlx after sc administration, resulting in prolonged, elevated hRlx serum concentrations. hRlx has been shown to be effective in this model without BPP if it is administered by a multidose sc schedule. As has been observed with other protein therapeutics, the dosage regimen employed for hRlx delivery appears to be an important determinant of the expression of its pharmacodynamic effects.

Animals↗
PubMed1987

Human relaxin increases cyclic AMP levels in cultured anterior pituitary cells.

Although relaxin acts at several abdominal sites and mammary tissue associated with pregnancy and parturition, the scope of target tissues and the signals conveying the relaxin message into the cell are poorly defined. We found that human relaxin rapidly elevates the cyclic AMP content of cultured rat anterior pituitary cells. This is a graded response (EC50 0.3 nM relaxin) that can be blocked by anti-relaxin antibodies or the hormones somatostatin and dopamine. Furthermore, other hormones with some sequence homology to relaxin, such as insulin and insulin-like growth factor-I, have no such action. We conclude that the anterior pituitary may be a target tissue for relaxin and that cyclic AMP may act as an intracellular messenger for relaxin in these cells.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Cellular catabolism of recombinant tissue-type plasminogen activator. Identification and characterization of a novel high affinity uptake system on rat hepatocytes.

The uptake, internalization, and intracellular degradation of 125I-labeled recombinant tissue-type plasminogen activator (rt-PA) by isolated rat hepatocytes was investigated. Incubation at 37 degrees C resulted in internalization of 125I-rt-PA, followed by the appearance of labeled trichloroacetic acid-soluble material in the incubation media due to degradation of rt-PA. Degradation of rt-PA was inhibited by the presence of NH4Cl (10 mM) or chloroquine (1 mM) (lysosomal tropic agents) in the incubation media. This suggests that rt-PA degradation occurs intracellularly, perhaps within the lysosomes. 125I-rt-PA was taken up by rat hepatocytes through a specific, high affinity mechanism with half-maximal uptake at 10 nM. Uptake of 125I-rt-PA was not inhibited by glycopeptides isolated from rt-PA nor by several other glycoproteins known to be cleared by identified hepatic receptors. These results suggest that the uptake of rt-PA by rat hepatocytes involves a receptor specific for t-PA and is not mediated by a carbohydrate-specific receptor.

Animals↗
PubMed1986

Behavioral changes following central injection of cysteamine in rats.

When tested 3 days following 4 daily intracerebroventricular injections of 250 micrograms cysteamine, which depletes somatostatin, rats demonstrated a significant increase in locomotor activity that was not observed in animals treated similarly with 350 micrograms cysteamine. A significant deficit in passive avoidance was observed in animals treated with the 350-micrograms dose, but not in animals treated with 250 micrograms cysteamine. These data suggest that altered activity of the somatostatinergic system disrupts specific processes underlying neural integration of complex behaviors.

Animals↗
PubMed1985

The acute effects of methamphetamine, amphetamine and p-chloroamphetamine on the cortical serotonergic system of the rat brain: evidence for differences in the effects of methamphetamine and amphetamine.

Cortical tryptophan hydroxylase (TPH) activity was reduced 3 h after a 10 or 15 mg/kg i.p. dose of either amphetamine (AMP), methamphetamine (METH), or p-chloroamphetamine (PCA). These injections of METH or PCA also decreased cortical serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations; none of the four doses of AMP decreased indoleamine concentrations. The time course of the effects following a 15 mg/kg dose of each amine was also different. Cortical TPH activity was reduced by all three amines for periods up to 24 h, whereas only METH and PCA significantly decreased 5-HT and 5-HIAA concentrations for long periods. These data suggest that each of the amphetamines may inhibit TPH activity, whereas only METH and PCA produced long-lasting decreases in indoleamine concentrations, reflecting either varying degrees of toxicity or differential effects of AMP on enzyme activity and neurotransmitter concentrations.

Amphetamine↗
PubMed1985

Blood pressure following microinjection of somatostatin related peptides into the rat nucleus tractus solitarii.

The possible role of medullary somatostatin as a neurotransmitter involved in blood pressure regulation was examined. Blood pressure and heart rate were measured in pentobarbital anesthetized rats while pmol quantities of somatostatin-28 (SS28), SS28-(15-28) (somatostatin-14), SS28-(1-12) or SS28-(1-10) were injected into the caudal nucleus tractus solitarii (NTS). Injection of artificial cerebrospinal fluid (ACSF; 500 nl/10 s) alone was followed by a small (2 mmHg) statistically insignificant decrease in blood pressure. SS28, SS28-(15-28) or SS28-(1-12) induced an immediate and statistically significant decrease in blood pressure as compared to vehicle alone. SS28-(1-10) had no significant effect. SS28 was tested at three doses. The lowest dose of SS28 (2.5 pmol) induced an 8 mmHg drop in blood pressure, the medium dose (25 pmol), an 11 mmHg drop and the highest dose (250 pmol) a 16 mmHg drop. The other peptide fragments were tested only at the higher 250 pmol dose. SS28-(1-12) induced a significantly (P less than 0.01) less drop in blood pressure (10 mmHg) when compared to either SS28 or SS28-(15-28) (18-19 mmHg). The hypotensive and bradycardiac effects of SS28 were prevented by pretreatment with methylscopolamine (5 mg/kg i.p.) 10 min prior to SS28. The cardiovascular effects of intramedullary injected SS28 were also blocked with an ipsilateral NTS injection of yohimbine or tolazoline 10 min prior to SS28.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Somatostatin-28 [1-12]-like peptides.

The search for a peptide corresponding to the NH2-terminus of somatostatin-28 (SS-28) in tissues has led to the isolation and characterization of somatostatin-28[1-12] from pancreas and hypothalamus. Somatostatin-28[1-12]-like immunoreactivity [SS-28 [1-12]-LI] is widely distributed throughout the central nervous system and the digestive system of rodents and primates, reaching levels comparable to those of somatostatin-14 (SS-14). Antibodies directed against the C-terminal end of the dodecapeptide are more specific and constitute excellent markers for the "prosomatostatin" system in mammalian tissues. In rat brain, SS-28[1-12]-LI material is highly concentrated in nerve fibres and terminals, especially in the median eminence, layer I of neocortex, the outer molecular layer of the dentate gyrus and the striatum. Additionally, immunoreactivity is observed in large multipolar or occasionally pyramidal-like neurons of the neocortex. SS-28[1-12] is secreted from hypothalamus and amygdala by a calcium dependent mechanism. No biological role is presently known for the dodecapeptide. Two other peptides of Mr = 8000 (8 K) and Mr = 5000 (5 K) which contain SS-28[1-12] at their carboxy-termini are present in acid extracts from rat pancreas, brain and spinal cord. These two peptides were isolated from an acid extract of rat brains using ion-exchange chromatography, gel permeation chromatography and reverse-phase HPLC. Results from amino acid analysis and partial sequencing were compared to the sequence of the cDNA encoding rat pre-prosomatostatin (prepro-SS) and revealed that the 8 K peptide is a 76 amino acid molecule corresponding to prepro-SS[25-100] and that the 5K peptide, which contains 44 amino acids, corresponds to prepro-SS [57-100]. The 5 K peptide was generated after cleavage of a Leu-Leu bond at position 56-57 of prepro-SS. The four most predominant peptides of the "prosomatostatin system" presently characterized are: SS-14, SS-28[1-12], SS-28 and prepro-SS[25-100]. Studies on pooled perfusates from rat hypothalamic tissue show that prepro-SS[25-100] is released with SS-28[1-12] in vitro and accounts for 22% of the total SS-28[1-12]-like immunoreactive material released during depolarization. The 5 K peptide is apparently not secreted. The presence of prepro-SS[25-100] in brain implies that, first, prosomatostatin can serve as an immediate precursor for SS-14 without going through SS-28 as an intermediate step and second, other peptides could conceivably be derived from the cryptic portion of the precursor.

Amygdala↗