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:BackgroundThere are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Methodology/principal findingsStable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.Conclusions/significanceThere are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation.

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-α, interleukin-1β & 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 β2-adrenoceptor (β2-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 β2-AR in down-regulating expression levels of the human α-synuclein gene SNCA and relative α-synuclein protein abundance. Given that α-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 α-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 α-synuclein gene expression and protein abundance in a β2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

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.