Pharmacological targeting of β₂‐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 β 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 β 2adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1β 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 β 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 β 2 -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.

Association between β2-Adrenoreceptor Medications and Risk of Parkinson’s Disease: A Meta-Analysis

“…By contrast, a β2AR antagonist, propranolol, increased the acetylation of H3k27 [ 12 ]. In a lipopolysaccharide (LPS) inflammatory PD rat model, β2AR stimulation reduced the motor deficits following intranigral LPS injection and decreased the loss of dopaminergic neuron and LPS-induced microgliosis in substantia nigra [ 22 ].…”

Role of G Protein-Coupled Receptors in Microglial Activation: Implication in Parkinson’s Disease

“…They found that a β 2 -selective agonist terbutaline but not a β 1 -selective agonist restrains the microglial proliferation via enhancing intracellular cAMP level ( Fujita et al, 1998 ). A number of studies reported that β 2 -adrenergic receptors inhibit microglia-mediated neuroinflammation via multiple signaling pathways to protect DA neurons from damage ( Qian et al, 2009 , 2011 ; Peterson et al, 2014 ; O’Neill et al, 2020 ). One of the studies showed that transformation from an M1- to M2-like phenotype in LPS-activated microglia by β 2 -adrenergic receptors agonists involves activation of the classical cAMP/PKA/CREB as well as the PI3K and p38 MAPK signaling pathways ( Sharma et al, 2019 ).…”

“…Another study reported that low doses of salmeterol inhibit microglial activation through a β 2 AR/β-arrestin2-dependent but cAMP/protein kinase A-independent pathway ( Qian et al, 2011 ). A recent study indicated that β 2 -adrenergic receptors activation using different agonists dramatically alleviates the progression of dopaminergic neurodegeneration via inhibiting microglial activation in the LPS-challenged inflammatory PD mouse model ( O’Neill et al, 2020 ).…”

Role of attribute selection on tuning the learning performance of Parkinson’s data using various intelligent classifiers

“…The For the statistical analysis, IBM SPSS V22 software was used, to find the correlation and coefficient using the mean, standard deviation, standard error, degree factors, significance was analysed by performing ANOVA descriptive analysis [49,50]]. To find the significance and relationship between groups, Turkey Honest Significance Difference (HSD) Post Hoc test was performed.…”

“…To find the significance and relationship between groups, Turkey Honest Significance Difference (HSD) Post Hoc test was performed. In our statistical analysis, the sample size was calculated using GPower 3.1 software [49]. The total sample size of 93 was taken divided into 3 groups such as SMOTE 31 samples, NEAR MISS 31 samples and IMBALANCE 31 samples were used.…”