Opposing effects of ß-2 and ß-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity.

BACKGROUND: Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson's disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored. In PD models and in human patients, ß-adrenergic receptors' (AR) signaling is associated with a reduction of neuroinflammation and PD pathology. However, the effect of NE depletion in the brain and the extent of NE and ß-ARs signaling involvement in neuroinflammation, and dopaminergic neuron survival is poorly understood. METHODS: Two mouse models of PD, a 6OHDA neurotoxin-based model and a human α-synuclein (hα-SYN) virus-based model of PD, were used. DSP-4 was used to deplete NE levels in the brain and its effect was confirmed by HPLC with electrochemical detection. A pharmacological approach was used to mechanistically understand the impact of DSP-4 in the hα-SYN model of PD using a norepinephrine transporter (NET) and a ß-AR blocker. Epifluorescence and confocal imaging were used to study changes in microglia activation and T-cell infiltration after ß1-AR and ß2-AR agonist treatment in the hα-SYN virus-based model of PD. RESULTS: Consistent with previous studies, we found that DSP-4 pretreatment increased dopaminergic neuron loss after 6OHDA injection. In contrast, DSP-4 pretreatment protected dopaminergic neurons after hα-SYN overexpression. DSP-4-mediated protection of dopaminergic neurons after hα-SYN overexpression was dependent on ß-AR signaling since using a ß-AR blocker prevented DSP-4-mediated dopaminergic neuron protection in this model of PD. Finally, we found that the ß-2AR agonist, clenbuterol, reduced microglia activation, T-cell infiltration, and dopaminergic neuron degeneration, whereas xamoterol a ß-1AR agonist showed increased neuroinflammation, blood brain barrier permeability (BBB), and dopaminergic neuron degeneration in the context of hα-SYN-mediated neurotoxicity. CONCLUSIONS: Our data demonstrate that the effects of DSP-4 on dopaminergic neuron degeneration are model specific, and suggest that in the context of α-SYN-driven neuropathology, ß2-AR specific agonists may have therapeutic benefit in PD.

ß-adrenergic modulation of discrimination learning and memory in the auditory cortex.

Despite vast literature on catecholaminergic neuromodulation of auditory cortex functioning in general, knowledge about its role for long-term memory formation is scarce. Our previous pharmacological studies on cortex-dependent frequency-modulated tone-sweep discrimination learning of Mongolian gerbils showed that auditory-cortical D1/5 -dopamine receptor activity facilitates memory consolidation and anterograde memory formation. Considering overlapping functions of D1/5 -dopamine receptors and ß-adrenoceptors, we hypothesised a role of ß-adrenergic signalling in the auditory cortex for sweep discrimination learning and memory. Supporting this hypothesis, the ß1/2 -adrenoceptor antagonist propranolol bilaterally applied to the gerbil auditory cortex after task acquisition prevented the discrimination increment that was normally monitored 1 day later. The increment in the total number of hurdle crossings performed in response to the sweeps per se was normal. Propranolol infusion after the seventh training session suppressed the previously established sweep discrimination. The suppressive effect required antagonist injection in a narrow post-session time window. When applied to the auditory cortex 1 day before initial conditioning, ß1 -adrenoceptor-antagonising and ß1 -adrenoceptor-stimulating agents retarded and facilitated, respectively, sweep discrimination learning, whereas ß2 -selective drugs were ineffective. In contrast, single-sweep detection learning was normal after propranolol infusion. By immunohistochemistry, ß1 - and ß2 -adrenoceptors were identified on the neuropil and somata of pyramidal and non-pyramidal neurons of the gerbil auditory cortex. The present findings suggest that ß-adrenergic signalling in the auditory cortex has task-related importance for discrimination learning of complex sounds: as previously shown for D1/5 -dopamine receptor signalling, ß-adrenoceptor activity supports long-term memory consolidation and reconsolidation; additionally, tonic input through ß1 -adrenoceptors may control mechanisms permissive for memory acquisition.

Bidirectional influence of amygdala ß1-adrenoceptors blockade on cannabinoid signaling in contextual and auditory fear memory.

The basolateral amygdala (BLA) is a major target and modulator of stress and has a critical role in the neural circuitry presenting learned fear behaviors. On the other hand, both the endocannabinoid and noradrenergic systems may be involved in regulating the stress responses, fear, and anxiety. Considering the aforementioned, we have investigated the involvement of the BLA ß1-adrenoceptors in conditioned fear responses induced by ACPA, a CB1 receptor (CB1R) agonist. In adult male NMRI mice, freezing responses to context and cue were measured using a Pavlovian fear conditioning apparatus. Pre-training intra-BLA microinjection of xamoterol (0.01 and 0.02 µg/mouse), a partial ß1-adrenoceptor agonist, or atenolol (0.5 µg/mouse), a ß1-adrenoceptor antagonist, decreased freezing behavior, which suggests an impairment of contextual and auditory fear retrieval. Similar results were found with pre-training intraperitoneal administration of ACPA (0.5 mg/kg). A sub-threshold dose of xamoterol, infused into the BLA, decreased ACPA (0.005 and 0.05 mg/kg) effect on both memories, while atenolol increased ACPA response to the context at the middle dose and decreased ACPA response to the tone at the lower dose. It can be concluded that the blockade of BLA ß1-adrenoceptors differentially affects ACPA response on the contextual and auditory conditioned fear memories.

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist.

Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the ß-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-α production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFß) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD.

Alterações eletrofisiológicas e ecocardiográficas agudas do xamoterol em pacientes chagásicos crônicos com disfunçäo do nó sinusal / Acute Electrophysiologic and Echocardiogrophic Effects of Xamoterol in Long-term Chagasic Patients With tinus Nodal Dysfunction

PURPOSE: To evaluate xamoterol (Corwin)--a partial beta-adrenergic receptor agonist--in long-term chagasic patients with symptomatic sinus node dysfunction previously treated with permanent atrial pacemaker. METHODS: Ten patients with permanent AAI pacing were studied. Initially, in spontaneous rhythm (sinus rhythm due to inhibition of the pacemaker) and under atrial pacing with rate of 60, 80 and 100ppm with temporary external programming of the pulse generator were evaluated. Basic heart rate, maximal sinus node recovery time and the point at which Wenckebach AV block was achieved were recorded. After that, echocardiographic evaluation was performed to analyze the left ventricular performance with ejection fraction calculation and the percentage of the fractional shortening during spontaneous rhythm and under atrial pacing with rate of 60, 80 and 100ppm. This protocol was repeated after 5mg of intravenous xamoterol. RESULTS: Five men and 5 women (mean age of 46) were studied. Xamoterol increased the basic heart rate, the rate at which the Wenckebach AV block was achieved and shortened the maximal sinus node recovery time (statistically significant) suggesting a beta-adrenergic agonist action of the drug. Left ventricular performance showed significant improvement only when the values in sinus rhythm (during inhibition of the pulse generator) were compared. Under atrial pacing, left ventricular function was consistently improved in all patients but with no significance. CONCLUSION: Xamoterol showed to be a beta-adrenergic receptors agonist in long-term chagasic patients with sinus node dysfunction at rest, when the simpatic tone was low, with evident action on the electrophysiologic parameters

Objetivo - Avaliar a ação do xamoterol (Corwin) -droga agonista parcial dos receptores b-adrenérgicos -em chagásicos crônicos com disfunção do nó sinusal sintomática e conseqüentemente portadores de marcapasso para estimulação atrial definitiva. Métodos: - Foram avaliados 10 pacientes (5 homens e 5 mulheres, idade média 46 anos) em rítmo sinusal basal (marcapasso inibido) e nas freqüências de 60, 80 e 100ppm, com reprogramação externa do gerador, estudando-se a freqüência do rítmo sinusal, o tempo de recuperação do nó sinusal e o ponto de Wenckebach. A seguir foram submetidos a avaliação ecocardiográfica para análise do desempenho sistólico do ventrículo esquerdo, com cálculo da fração de ejeção e da percentagem de encurtamento fracional durante rítmo espontâneo basal e nas freqüências de 60, 80 e 100ppm. Todo esse protocolo foi feito antes e após injeção endovenosa de 5 mg de xamoterol Resultados - Houve aumento estatisticamente significante da freqüência cardíaca sinusal basal e da freqüência em que surgia bloqueio A V do 20 grau do tipo I (ponto de Wenckebach) e diminuição, também estatisticamente significante do tempo de recuperação do nó sinusal, sugerindo uma ação b-adrenérgica agonista sobre os parâmetros eletrofisiológicos. A função ventricular melhorou significantemente apenas quando foram comparados os valores em rítmo sinusal basal (marcapasso inibido), antes e após o xamoterol. Sob ação do marcapasso em outras freqüências, houve incremento consistente do desempenho sistólico do ventrículo esquerdo em todos os pacientes mas sem significado estatístico. Conclusão: Xamoterol mostrou ser uma droga badrenérgica agonista parcial em chagásicos crônicos quando o tono simpático está baixo, com ação mais marcante sobre os parâmetros eletrofisiológicos