The potential of insulin-like growth factor-I as a therapeutic for the treatment of neuromuscular disorders.
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
J L Vaught
Publications and source records attributed to J L Vaught.
rhIGF-I enhances functional recovery from sciatic crush. Time-course and dose-response study.
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Animals↗
Pharmacological induction of nerve growth factor mRNA in adult rat brain.
Three structurally unrelated compounds, all of which induce nerve growth factor (NGF) in cell culture systems, were assessed for their ability to induce NGF mRNA in adult rat brain using a highly sensitive RNAse protection assay. Interleukin-1 beta (0.5-1 pmol) and 1,25-dihydroxyvitamin D3 (25-25,000 pmol) were extremely potent inducers of NGF mRNA, being respectively at least 50,000 and 4000 times more potent than 4-methylcatechol. These compounds elicited an approximate twofold increase in NGF mRNA in both the hippocampus and cortex, without altering beta-actin mRNA levels after a single intracerebroventricular injection. The duration of NGF induction was dependent on the compound administered. For example, the elevation of NGF mRNA elicited by interleukin-1 beta peaked at 8 h and lasted for at least 24 h. In contrast, the induction of NGF after 1,25-dihydroxyvitamin D3 and 4-methylcatechol administration peaked between 4 and 8 h and was not apparent 24 h after injection. These results demonstrate induction of NGF mRNA in vivo by administration of physiological or pharmacological agents and differentiate these agents by potency and duration of action. Further, these findings indicate that pharmacological induction of NGF may be a viable strategy for the treatment of neurodegenerative disorders such as Alzheimer's disease.
Animals↗
Insulin-like growth factor-I: potential for treatment of motor neuronal disorders.
Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.
Amino Acid Sequence↗
The combined immunological and antinociceptive defects of beige-J mice: the possible existence of a 'mu-repressin'.
A selective non-responsiveness to the analgesic effects of opioid mu receptor-, but not opioid delta receptor-, mediated antinociception in the tail-flick test has been identified in C57BL/6J-bgJ (beige-J) mice. The beige-J mutation is also known to give rise to multiple immunological disorders and immune cell dysfunctions. A link between these apparently disparate manifestations has been examined in a series of studies using, for example, adoptive transfer of spleen cells. The findings appear to have broad implications for the link between the immune and opioid systems.
Animals↗
Aurintricarboxylic acid protects hippocampal neurons from NMDA- and ischemia-induced toxicity in vivo.
The polymeric dye aurintricarboxylic acid (ATA) has been shown to protect various cell types from apoptotic cell death, reportedly through inhibition of a calcium-dependent endonuclease activity. Recent studies have indicated that there may be some commonalities among apoptosis, programmed cell death, and certain other forms of neuronal death. To begin to explore the possibility of common biochemical mechanisms underlying ischemia- or excitotoxin-induced neuronal death and apoptosis in vivo, gerbils or rats subjected to transient global ischemia or NMDA microinjection, respectively, received a simultaneous intracerebral infusion of ATA or vehicle. As a biochemical marker of neuronal death, spectrin proteolysis, which is mediated by activation of calpain I, was measured in hippocampus after 24 h. ATA treatment resulted in a profound reduction of both NMDA- and ischemia-induced spectrin proteolysis, consistent with the possibility of some common mechanism in apoptosis and other forms of neuronal death in vivo.
Animals↗
Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.
Acetylcholine↗
Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain.
The deposition of amyloid in senile plaques and along the walls of the cerebral vasculature is a characteristic feature of Alzheimer disease. The peptide comprising the carboxyl-terminal 100 amino acids of the beta-amyloid precursor protein (beta APP) has been shown to aggregate into amyloid-like fibrils in vitro and to be neurotoxic, suggesting that this fragment may play a role in the etiology of Alzheimer disease. To address this question, we expressed this carboxyl-terminal 100-amino acid peptide of beta APP in transgenic mice under the control of the brain dystrophin promoter. We used an antibody to the principal component of amyloid, beta/A4, to demonstrate cell-body and neuropil accumulation of beta/A4 immunoreactivity in the brains of 4- and 6-month-old transgenic mice. Only light cytoplasmic staining with this antibody was visible in control mice. In addition, immunocytochemical analysis of the brains with an antibody to the carboxyl terminus of beta APP revealed abnormal aggregation of this epitope of beta APP within vesicular structures in the cytoplasm and in abnormal-appearing neurites in the CA2/3 region of the hippocampus in transgenic mice, similar to its aggregation in the cells of Alzheimer disease brains. Thioflavin S histochemistry suggested accumulations of amyloid in the cerebrovasculature of transgenic mice with the highest expression of the beta APP-C100 transgene. These observations suggest that expression of abnormal carboxyl-terminal subfragments of beta APP in vivo may cause amyloidogenesis and specific neuropathology.
Amyloid beta-Protein Precursor↗
2-Substituted 1-azabicycloalkanes, a new class of non-opiate antinociceptive agents.
2-Substituted 1-azabicycloalkanes (3- and 5-aryloctahydroindolizines 2 and 11, 3-cyclohexyloctahydroindolizine 12, 4-aryloctahydroquinolizines 13, and 3-arylhexahydropyrrolizines 14) constitute a new class of non-opiate antinociceptive agents. These compounds demonstrated activity in the mouse abdominal constriction test and many were active in the mouse tail-flick test. trans-3-(2-Bromophenyl)octahydroindolizine (2a) did not bind to the opiate receptor nor did it affect arachidonate metabolism. 3-Aryloctahydroindolizines were prepared by catalytic hydrogenation of 1-aryl-3-(2-pyridinyl)-2-propen-1-ones. The X-ray crystal structure of (-)-2a was determined and absolute stereochemistry assigned as 3-R,8a-R.
Analgesics↗
Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity.
The Ki values for etoperidone, trazodone and MCPP (m-chlorophenylpiperazine dihydrochloride) at 5-HT1A sites (using rat cerebral cortical synaptosomes and [3H]8-OH-DPAT) were determined to be 20.2, 23.6 and 18.9 nM, respectively. In an effort to elucidate the functional nature of the interaction at 5-HT1A sites in vivo, the ability of each compound to elicit reciprocal forepaw treading (RFT) or to block the RFT induced by 8-OH-DPAT in reserpinized rats was tested. Specifically, 8-OH-DPAT (1.0 mg/kg SC)-challenged or non-challenged (control) reserpinized (1.0 mg/kg SC) rats were administered etoperidone, trazodone or MCPP (IP) and scored for the elicitation of RFT (indicative of 5-HT1A agonistic activity) or for block of RFT induced by 8-OH-DPAT (indicative of 5-HT1A antagonistic activity). Reference compounds confirmed the specificity of the test. We report that etoperidone, trazodone and MCPP inhibited 8-OH-DPAT-induced RFT (ID50 = 17.4, 23.8 and 13.4 mg/kg, respectively). Only marginal RFT was produced in non-challenged animals by etoperidone and trazodone at a high dose (40 mg/kg). Taken together, the results suggest a predominant antagonistic activity of etoperidone, trazodone and MCPP at 5-HT1A receptor sites in rat central nervous system. However, one cannot rule out the possibility that these compounds are weak partial agonists. This activity may be relevant to the antidepressant action of these compounds.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.
Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects.
Animals↗
Centrally-mediated antinociceptive action of RWJ-22757 (formerly McN-5195): involvement of spinal descending inhibitory pathways (an hypothesis).
The present studies were an attempt to examine the mechanism of action of the novel antinociceptive compound RWJ-22757, (+/-)-trans-3-(2-bromophenyl)-octahydroindolizine (McN-5195). Intracerebroventricular (i.c.v.) administration of RWJ-22757 produced dose-related antinociception in the mouse tail-flick (48 degrees C) and rat hot-plate (51 degrees C) tests (ED50 = 243.3 and 261.3 micrograms, respectively). In contrast, intrathecal (i.t.) administration was without effect. The antinociception produced by peripherally (i.p.) or centrally (i.c.v.) administered RWJ-22757 was attenuated by i.t. administration of 2 micrograms phentolamine, 5 micrograms yohimbine, or 10 micrograms methysergide. I.t. administration of naloxone, at a dose (0.5 micrograms) that significantly attenuated the antinociceptive effects of peripherally or centrally administered morphine, had no effect on RWJ-22757-induced antinociception. We conclude from these results, coupled with the overall pharmacological and neurochemical profile of RWJ-22757, that the data are consistent with the hypothesis that RWJ-22757 produces antinociception predominantly at a site or sites located supraspinally with little or no activity at the spinal level and that RWJ-22757 activates adrenergic and serotonergic descending inhibitory pathways, increasing the tonic activity of endogenous antinociceptive systems.
Analgesics↗
The novel anticonvulsant loreclezole (R 72063) does not produce diazepam-like anterograde amnesia in a passive avoidance test in rats.
Rats were injected intraperitoneally with loreclezole (R 72063), diazepam, or scopolamine 60 min prior to acquisition of a passive avoidance task and tested 18 h later for retention of the learned (passive) behavior. The known impairment of performance produced by diazepam in this test is believed to be a model for the clinically observed diazepam-induced anterograde amnesia in humans. We report in this study that (1) consistent with the literature, pretreatment with diazepam (2.0-16.0 mg/kg i.p.) or scopolamine (3.0 mg/kg i.p.) produced impairment in passive avoidance performance of rats (anterograde amnesia), but (2) pretreatment with loreclezole (R 72063) (2.0-80.0 mg/kg i.p.) did not impair the acquisition, retention, or the retrieval (tested 18 h later) of passive avoidance behavior by rats at any dose. The results suggest that the anticonvulsant activity of loreclezole is mediated by a mechanism distinct from the one coupled to diazepam-like disruption of cognitive functions involved in the acquisition or posttraining information processing of passive avoidance behavior.
Amnesia↗
Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
Animals↗
Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action.
McN-5195 [(+/-)-trans-3-(2-bromophenyl)-octahydroindolizine] inhibited at nontoxic doses the nociceptive response in tail-pinch, tail-flick and 48 degrees C hot-plate tests of mice, with ED50 values of 38.2, 33.9 and 30.9 mg/kg i.p., respectively, and of rats, with ED50 values (i.p.) of 33.2 mg/kg (tail-flick) and 33.3 mg/kg (hot-plate). The compound was p.o. active in the acetylcholine-induced irritant test (ED50 = 20.1 mg/kg) in mice and the air-induced irritant test (ED50 = 33.2 mg/kg) in rats. McN-5195 blocked thalamic activity (multiunit recordings from the ventral posterolateral nucleus) evoked by noxious stimulation of the contralateral hindlimb of anesthetized rats, but did not alter thalamic activity during non-noxious stimulation. The antinociceptive action of McN-5195 was not blocked by naloxone and was not diminished in morphine-tolerant animals. McN-5195 did not affect arachidonate metabolism and was not active against carrageenan-induced paw edema or in an adjuvant arthritis test in rats. McN-5195 did not bind to opiate, serotonin S1 or S2, dopamine D2, alpha-1, alpha-2, beta adrenergic or gamma-aminobutyric acid-A receptors and did not inhibit the synaptic uptake of norepinephrine, serotonin, dopamine or gamma-aminobutyric acid. McN-5195-induced antinociception was not affected by reserpine or phentolamine pretreatment and was not reduced in clonidine-tolerant animals. Ketanserin and yohimbine inhibited McN-5195-induced antinociception by an indirect mechanism. Tolerance did not develop to chronic administration of McN-5195 (120 mg/kg 3 times per day for 10 days). We conclude that McN-5195 is a structurally novel (indolizine) antinociceptive agent that produces its analgesic action via a nonopioid mechanism, not involving products of arachidonate metabolism.
Analgesics↗
Modulation of mu-mediated antinociception by delta agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2,D-Pen5]enkephalin.
The effect of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the mu agonists morphine, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO), [NMePhe3,D-Pro4]morphiceptin (PLO17), beta-endorphin, phenazocine, etorphine and sufentanil was studied in mice. Only the antinociceptive effects of morphine and normorphine were modulated by i.c.v. coadministration of a dose of DPDPE which did not produce any significant antinociception alone. Both the morphine and normorphine dose-response lines were displaced to the left in the presence of DPDPE. The delta-selective antagonist ICI174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is alpha-aminoisobutyric acid) blocked the modulation of morphine antinociception by DPDPE. ICI 174,864 alone failed to produce either a significant increase or decrease of morphine, phenazocine, etorphine or beta-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the mu receptor; such modulation may come about via the existence of an opioid mu-delta receptor complex. The mu receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other mu agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal mu receptor-mediated antinociception.
Animals↗
Can equal pA2 values be compatible with receptor differences?
Situations exist in which pA2 analysis leads to conclusions about receptor differentiation that conflict with those drawn from other convincing lines of evidence. Robert Raffa and colleagues address this issue in its broadest context, particularly in relationship to the concept of accessory binding sites, using the controversy of delta-opioid receptor-mediated antinociception as an example. When the possibility of accessory binding sites is considered, it becomes clear that the finding of equal pA2 values does not necessarily mean action at the same receptor, and that the finding of unequal pA2 values does not necessarily confirm action at different receptors.
Chemical Phenomena↗
Substance P, neurokinin A, and neurokinin B induce generation of IL-1-like activity in P388D1 cells. Possible relevance to arthritic disease.
Near nanomolar concentrations of substance P induce production of IL-1 or an IL-1-like activity in the mouse macrophage cell line P388D1. Moreover, this could be accomplished with the carboxyl-terminal octapeptide substance P4-11, and could be inhibited with the substance P antagonist [D-Pro2, D-Trp7,9]-substance P. Two other mammalian neurokinins, neurokinin A and neurokinin B, were also found to induce secretion of IL-1-like activity in P388D1 cells. These findings suggest that activation of immune cells by neuromodulators can contribute to the maintenance of the chronic inflammatory state and the immunopathology observed in arthritic disease mediated by IL-1. The results also suggest that one approach to the treatment of rheumatoid arthritis might be to attempt to inhibit the local effects of immuno-modulatory neuropeptides, specifically the neurokinins, in affected joints.
Amino Acid Sequence↗