Dataset Information

Pharmacological targeting of ?₂ -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

ABSTRACT:

Background and purpose

Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD.

Experimental approach

The impact of treatment with the ?₂ -adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed.

Key results

LPS-induced deficits in motor function (akinesia and forelimb-use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co-treatment with the ?₂ -adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1? production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment.

Conclusion and implications

The results indicate that pharmacologically targeting ?₂ -adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as ?₂ -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.

SUBMITTER: O'Neill E

PROVIDER: S-EPMC6989960 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Pharmacological targeting of β<sub>2</sub> -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

O'Neill Eoin E Yssel Justin D JD McNamara Caoimhe C Harkin Andrew A

British journal of pharmacology 20191212 2

<h4>Background and purpose</h4>Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD.<h4>Experimental approach</h4>The impact of treatment with the β<sub>2</sub> -adrenoceptor agonists clenbuterol and formoterol ...[more]

PMID: 31506926

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Project description:Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson's disease (PD), whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflammatory mediator production (e.g., tumor necrosis factor-?, interleukin-1? & inducible nitric oxide synthase activity), thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflammatory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to ?2-adrenoceptor (?2-AR) stimulation via the production of growth factors (e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor & glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the ?2-AR in down-regulating expression levels of the human ?-synuclein gene SNCA and relative ?-synuclein protein abundance. Given that ?-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson's disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of ?-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via (1) inhibiting nigral microglial activation & pro-inflammatory mediator production, (2) promoting the synthesis of neurotrophic factors from midbrain astrocytes and (3) downregulating ?-synuclein gene expression and protein abundance in a ?2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial ?2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

Project description:Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

Dataset Information

Pharmacological targeting of ?₂ -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Pharmacological targeting of β<sub>2</sub> -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Pharmacological targeting of ?2 -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Pharmacological targeting of β<sub>2</sub> -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pharmacological targeting of ?₂ -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.