Catecholaminergic based therapies for functional recovery after TBI.

Among the many pathophysiologic consequences of traumatic brain injury are changes in catecholamines, including dopamine, epinephrine, and norepinephrine. In the context of TBI, dopamine is the one most extensively studied, though some research exploring epinephrine and norepinephrine have also been published. The purpose of this review is to summarize the evidence surrounding use of drugs that target the catecholaminergic system on pathophysiological and functional outcomes of TBI using published evidence from pre-clinical and clinical brain injury studies. Evidence of the effects of specific drugs that target catecholamines as agonists or antagonists will be discussed. Taken together, available evidence suggests that therapies targeting the catecholaminergic system may attenuate functional deficits after TBI. Notably, it is fairly common for TBI patients to be treated with catecholamine agonists for either physiological symptoms of TBI (e.g. altered cerebral perfusion pressures) or a co-occuring condition (e.g. shock), or cognitive symptoms (e.g. attentional and arousal deficits). Previous clinical trials are limited by methodological limitations, failure to replicate findings, challenges translating therapies to clinical practice, the complexity or lack of specificity of catecholamine receptors, as well as potentially counfounding effects of personal and genetic factors. Overall, there is a need for additional research evidence, along with a need for systematic dissemination of important study details and results as outlined in the common data elements published by the National Institute of Neurological Diseases and Stroke. Ultimately, a better understanding of catecholamines in the context of TBI may lead to therapeutic advancements. This article is part of a Special Issue entitled SI:Brain injury and recovery.

Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans.

Monoamines and neuropeptides interact to modulate most behaviors. To better understand these interactions, we have defined the roles of tyramine (TA), octopamine, and neuropeptides in the inhibition of aversive behavior in Caenorhabditis elegans. TA abolishes the serotonergic sensitization of aversive behavior mediated by the two nociceptive ASH sensory neurons and requires the expression of the adrenergic-like, Gαq-coupled, TA receptor TYRA-3 on inhibitory monoaminergic and peptidergic neurons. For example, TA inhibition requires Gαq and Gαs signaling in the peptidergic ASI sensory neurons, with an array of ASI neuropeptides activating neuropeptide receptors on additional neurons involved in locomotory decision-making. The ASI neuropeptides required for tyraminergic inhibition are distinct from those required for octopaminergic inhibition, suggesting that individual monoamines stimulate the release of different subsets of ASI neuropeptides. Together, these results demonstrate that a complex humoral mix of monoamines is focused by more local, synaptic, neuropeptide release to modulate nociception and highlight the similarities between the tyraminergic/octopaminergic inhibition of nociception in C. elegans and the noradrenergic inhibition of nociception in mammals that also involves inhibitory peptidergic signaling.

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs.

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 µg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica.

BACKGROUND: The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s) to which catecholamines (norepinephrine, epinephrine and dopamine) may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. RESULTS: Use of specific catecholamine receptor antagonists revealed that only alpha, and not beta, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. CONCLUSION: The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

Involvement of monoaminergic system in the antidepressant-like effect of the hydroalcoholic extract of Siphocampylus verticillatus.

The antidepressant-like effect of the hydroalcoholic extract obtained from aerial parts of Siphocampylus verticillatus, a Brazilian medicinal plant, was investigated in two models of depression in mice and against synaptosomal uptake of serotonin, noradrenaline and dopamine. The immobility times in the forced swimming test (FST) and in the tail suspension test (TST) were significantly reduced by the extract (dose range 100-1000 mg/kg, i.p.), without accompanying changes in ambulation when assessed in an open-field. In addition when given orally the extract was also effective in reducing the immobility time in the TST. The efficacy of extract in the TST was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg, i.p.) and with fluoxetine (32 mg/kg, i.p.). The anti-immobility effect of the extract (600 mg/kg, i.p.) assessed in the TST was not affected by pre-treatment with naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, i.p., a nitric oxide precursor). In contrast, the extract (600 mg/kg, i.p.) antidepressant-like effect was significantly reduced by pre-treatment of animals with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis), sulpiride (50 mg/kg, i.p., a selective D2 receptor antagonist), prazosin (62.5 microg/kg, i.p., an alpha1 adrenoreceptor antagonist) or by guanosine 5'-monophosphate (GMP, 250 mg/kg, i.p., a nucleotide known to block some actions elicited by NMDA). The biochemical data show that the extract of S. verticillatus inhibited in a graded manner the uptake of monoamines. However, at the IC50 level, the extract was approximately 3.2 to 3.4-fold more potent and also more efficacious in inhibiting the synaptosomal uptake of noradrenaline and serotonin than dopamine. Taken together these data demonstrate that the extract of S. verticillatus elicited a significant antidepressant-like effect, when assessed in the TST and FST in mice. Its action seems to involve an interaction with adrenergic, dopaminergic, glutamatergic and serotonergic systems.

Lipopolysaccharide-induced tumor necrosis factor-alpha release is controlled by the central nervous system.

OBJECTIVE: Lipopolysaccharide (LPS) injection in mammals orchestrates the release of many proinflammatory and anti-inflammatory cytokines. Intravenous administration of 0.2 mg/kg of LPS into unanesthetized rats with indwelling jugular catheters provoked a rapid, 50-fold increase in plasma tumor necrosis factor (TNF)-alpha within 30 min, which declined by 60% by 120 min. To test our hypothesis that such a rapid increase of TNF-alpha would be either neurally or hormonally controlled, the effect on TNF-alpha release of anesthesia (ketamine/acepromazine/xylazine) and catecholaminergic agonists and antagonists, either alone or in the presence of LPS, was determined. METHODS: Rats bearing indwelling external jugular catheters were injected with the test drug or saline after removal of 0.6 ml of blood (-10 min). At time zero, LPS or saline was administered. Thereafter, blood samples were drawn at 15, 30, 120, 240 and 360 min. TNF-alpha was measured by immunoassay. RESULTS: Among all the drugs tested, only propranolol increased plasma TNF-alpha. Anesthesia significantly blunted the LPS-induced TNF-alpha peak by 50%. Isoproterenol, a beta-adrenergic agonist, also blocked LPS-induced TNF-alpha release by 70% at 30 min and 90% at 120 min. On the contrary, propranolol, a beta-receptor blocker, induced a highly significant 3-fold increase in plasma TNF-alpha concentrations at 30 min and augmented the response to LPS 2-fold after endotoxin injection. Phentolamine, an alpha-receptor blocker, decreased the LPS-induced TNF-alpha release by 57% at 30 min. Similarly, alpha-bromoergocryptine, a dopamine D2 receptor agonist, decreased the LPS-induced TNF-alpha peak by 70% at 30 min and 50% at 120 min. CONCLUSIONS: We conclude that TNF-alpha is at least in part neurally controlled since the anesthetic blocked its response to LPS. The fact that isoproterenol decreased the LPS-induced TNF-alpha release, whereas propranolol augmented basal and LPS-induced release suggests that the sympathetic nervous system inhibits basal and LPS-stimulated TNF-alpha release via beta-adrenergic receptors. Since phentolamine blocked LPS-induced release, this release may be induced, in part at least, by LPS-stimulated adrenergic drive acting on alpha-adrenergic receptors. The suppressive action of bromoergocryptine, a dopamine D2 receptor agonist, on LPS-induced TNF-alpha release may be mediated in part by suppression of prolactin release, which triggers TNF-alpha release.

Dopamine induces intracellular Ca2+ signals mediated by alpha1B-adrenoceptors in rat pineal cells.

We have studied the functional interaction of dopamine with alpha1-adrenoceptor subtypes by measuring intracellular Ca2+ levels in pineal cells, a cell type where adrenoceptors are well characterized. We show that dopamine induces transient intracellular Ca2+ signals in only 70% of cells responding to phenylephrine. Dopamine-induced Ca2+ signals desensitise faster than Ca2+ transients elicited with phenylephrine and are selectively blocked by desipramine, imipramine, and alpha1B-adrenoceptor antagonists. These results suggest that dopamine induced Ca2+ signals are mainly due to the activation of one subtype of alpha-adrenoceptor, the alpha1B.

Influence of catecholamine receptor agonists and antagonists on the ultradian rhythm of the EEG in the posterior hypothalamus.

The power of delta and theta frequency bands of the EEG in the posterior hypothalamus of the rat fluctuates according to an ultradian rhythm. To investigate, whether catecholamine receptor ligands influence the ultradian EEG rhythm, drugs were applied intracerebroventricularly into the lateral ventricle of anaesthetized rats. Injection of the alpha1-adrenoceptor agonist (+/-)-methoxamine (150 nmol) abolished, while 25 nmol of the compound prolonged the cycle duration of the rhythmic changes in the delta and theta frequency bands. Injected into the lateral ventricle, the alpha2-adrenoceptor agonists 6-ethyl-5,6,7,8-tetrahydro-4H-oxazol[4,5-d] azepin-2-amine (B-HT 933) or clonidine (150 nmol each) prolonged the duration of the cycles of both frequency bands. The beta1/2-receptor agonists (+/-)-orciprenaline (300 nmol) and (R)-(-)-isoprenaline (150 nmol) slowed down the cycle durations of both frequency bands. The beta1-receptor agonist (+/-)-xamoterol (300 nmol) also prolonged the cycle durations of the delta and theta frequency bands. The beta1-receptor antagonist (S)-(-)-atenolol was ineffective (150 and 300 nmol). The beta2-receptor agonist (+/-)-salbutamol (300 nmol) shortened the duration of the ultradian rhythm in the two frequency bands, while the beta2-receptor antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1 H-inden-4-yl) oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551) (300 nmol) exerted the opposite effect. On the other hand, the D1 receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-1H)-3-benzazepine-7,8-diol (SKF 38393) and the D2 agonist (4aR,8aR)-(-)-quinpirole (150 nmol each) slowed down the frequency of the ultradian rhythm. The powers of alpha and beta frequency bands were not significantly influenced by the catecholamine receptor ligands used in this study. The findings suggest that, in the posterior hypothalamus, the ultradian rhythm of the delta and theta frequency bands are prolonged when beta1-receptors are stimulated and shortened on stimulation of beta2-adrenoceptors. Endogenous catecholamines released from their neurons seem to shorten the duration of the rhythmic fluctuations by stimulating beta2-receptors and to slow down the frequency of the cyclic fluctuations by stimulating alpha2-adrenoceptors. The ultradian rhythm is also slowed down on stimulation of D1 and D2 receptors by endogenous dopamine. Together with previous observations, the results indicate that the ultradian EEG rhythm is susceptible to modulatory mechanisms mediated by catecholaminergic neurons.