Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson’s disease

Yssel, Justin; O’Neill, Eoin; Nolan, Yvonne M.; Connor, Thomas J.; Harkin, Andrew

doi:10.1016/j.bbi.2018.01.004

Cited by 23 publications

(23 citation statements)

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“…A recent publication using mutant mice characterized by the progressive degeneration of dopaminergic neurons demonstrated that chronic pharmacological NET blockade ameliorates such degeneration and the subsequent motor impairment (Kreiner et al, 2019). Peripheral administration of the NET blocker atomoxetine also reduced DA damage in a lipopolysaccharide inflammatory rat model of PD (Yssel et al, 2018). Direct noradrenergic damage by the administration of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (or DSP-4) also produces motor deficits and DA cell loss in control rats (Af Bjerkén et al, 2019).…”

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

“…Low concentrations of NA or long acting b 2 -agonists are able to inhibit the microglial production and release of chemokines, interleucines, tumor necrosis factor (TNF-a), superoxide or nitric oxide, among others, (Mori et al, 2002;McNamee et al, 2010a;Qian et al, 2011) or to stimulate the synthesis of interleukin-1 receptor antagonists (McNamee et al, 2010b). Pharmaceutical strategies for increasing NA levels also attenuate nigral microglial activation and ameliorate the behavioral deficits in parkinsonian rats (Yssel et al, 2018). Other authors have also proposed that in addition to the b 2mediated mechanisms, NA can impact inflammation by inhibiting NADPH oxidase-generated superoxide (Jiang et al, 2015).…”

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

“…Other authors have also proposed that in addition to the b 2mediated mechanisms, NA can impact inflammation by inhibiting NADPH oxidase-generated superoxide (Jiang et al, 2015). Additionally, b 2 -agonists and NET inhibitors can also induce release of neurotrophic factors from astrocytes promoting neuroprotection and regeneration (Yssel et al, 2018).…”

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

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The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

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The Noradrenergic System in Parkinson’s Disease

et al. 2020

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“…Microglial activation and release of pro‐inflammatory cytokines promote oxidative stress and toxicity are widely considered to contribute to the degeneration of the nigrostriatal tract (McGeer & McGeer, ; Tansey & Goldberg, ). Inflammatory‐based models of PD such as intranigral administration of the bacterial endotoxin and immune stimulus LPS simulate this process and provoke degeneration of dopamine neurons in the SN (Hoban et al, ; Yssel, O'Neill, Nolan, Connor, & Harkin, ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological targeting of β₂‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease

O’Neill

Yssel

McNamara

et al. 2019

British J Pharmacology

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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.

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“…Previously, it has been demonstrated by (Herrera, Castano, Venero, Cano, & Machado, 2000) and more recently replicated by (Yssel, O'Neill, Nolan, Connor, & Harkin, 2018) that a single unilateral intra-nigral injection of LPS induces a robust nigral microgliosis, dopaminergic neurodegeneration, nigrostriatal dopamine loss, and associated motor deficits in rats. Here we aim to focus on the role of astrocytes in inflammation-mediated Parkinsonism to investigate whether functional astrocytes protect against immune-mediated degeneration of the nigrostriatal dopaminergic system, or immunocompetent astroglia actively sustain a pro-inflammatory state and contribute to the neurodegenerative process in the intra-nigral LPS model of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 92%

L‐alpha‐aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

O’Neill

Goisis

Haverty

et al. 2019

J of Neuroscience Research

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Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra‐nigral lipopolysaccharide (LPS)‐induced experimental Parkinsonism in male Wistar rats via simultaneous co‐injection of the astrocytic toxin L‐alpha‐aminoadipic acid (L‐AAA). Simultaneous intra‐nigral injection of L‐AAA attenuated the LPS‐induced loss of tyrosine hydroxylase‐positive (TH+) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH+ dopaminergic nerve terminals in the striatum. L‐AAA also repressed LPS‐induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L‐AAA abrogated intra‐nigral LPS‐induced glial fibrillary acidic protein‐positive (GFAP+) reactive astrogliosis and attenuated the LPS‐mediated increases in nigral S100β expression levels in a time‐dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1‐positive (Iba1+) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.

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Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson’s disease

Cited by 23 publications

References 84 publications

The Noradrenergic System in Parkinson’s Disease

The Noradrenergic System in Parkinson’s Disease

Pharmacological targeting of β₂‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease

L‐alpha‐aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

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Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson’s disease

Cited by 23 publications

References 84 publications

The Noradrenergic System in Parkinson’s Disease

The Noradrenergic System in Parkinson’s Disease

Pharmacological targeting of β2‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease

L‐alpha‐aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

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Pharmacological targeting of β₂‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease