Effects of vagus nerve stimulation are mediated in part by TrkB in a parkinson’s disease model

Farrand, Ariana Q.; Helke, Kristi L.; Aponte-Cofresí, Luis; Göõz, Monika; Gregory, Rebecca; Hinson, Vanessa K.; Boger, Heather A.

doi:10.1016/j.bbr.2019.112080

Cited by 17 publications

(19 citation statements)

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“…In addition to depression and epilepsy, vagal stimulators have been already used in other chronic conditions such as chronic pain, refractory migraine and cardiovascular diseases, testifying to their safety profile [ 126 , 127 ]. Moreover, recent preclinical research on the cholinergic anti-inflammatory pathway is expanding the use of vagus nerve stimulation (VNS) to target neuroinflammation in neurological disorders such as Alzheimer’s disease, Parkinson’s disease and traumatic brain injuries [ 128 , 129 , 130 ]. Promising results are also shown in ischemic stroke models.…”

Section: Targeting the Vagus Nerve: A Promising Multilevel Approacmentioning

confidence: 99%

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke

Carandina

Lazzeri

Villa

et al. 2021

IJMS

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Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, prognosis of mid-term outcomes and response to recanalization therapy. In particular, the evaluation of the ANS function through the analysis of heart rate variability (HRV) appears to be a promising non-invasive and reliable tool for the management of patients with AIS. Furthermore, preclinical molecular studies on the pathophysiological mechanisms underlying the onset and progression of stroke damage have shown an extensive overlap with the activity of the vagus nerve. Evidence from the application of vagus nerve stimulation (VNS) on animal models of AIS and on patients with chronic ischemic stroke has highlighted the surprising therapeutic possibilities of neuromodulation. Preclinical molecular studies highlighted that the neuroprotective action of VNS results from anti-inflammatory, antioxidant and antiapoptotic mechanisms mediated by α7 nicotinic acetylcholine receptor. Given the proven safety of non-invasive VNS in the subacute phase, the ease of its use and its possible beneficial effect in hemorrhagic stroke as well, human studies with transcutaneous VNS should be less challenging than protocols that involve invasive VNS and could be the proof of concept that neuromodulation represents the very first therapeutic approach in the ultra-early management of stroke.

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Section: Targeting the Vagus Nerve: A Promising Multilevel Approacmentioning

confidence: 99%

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke

Carandina

Lazzeri

Villa

et al. 2021

IJMS

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“…The same double lesion PD model was utilized for these studies as previously implemented by our group (Fig. 1A) [10,30]. Lesion rats received DSP-4 (50 mg/kg, i.p., Sigma) followed 7 days later by intrastriatal 6-OHDA (6 mg/mL, 2 mL/site, made with 0.02% ascorbate, Sigma) at the following coordinates: Hole 1: AP:þ1.6, ML:±2.4, DV: -4.2; Hole 2: AP:þ0.2, ML:±3.7, DV: -5.0 [32].…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…Immunohistochemical staining was conducted on serial sections from the left striatum (every 12th) and bilateral LC (every 3rd) [10,30] to detect catecholamines using anti-TH (tyrosine hydroxylase, Pelfreez, 1:1000). Inflammation in the SN was assessed via serial sections (every 6th) to detect GFAP (glial fibrillary acidic protein stained astrocytes, Dako, 1:2000) and Iba-1 (ionized calcium-binding adaptor molecule-1 stained microglia, Wako, 1:1000).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Immunofluorescent staining was used to assess dopaminergic neurons by detecting TH (Abcam, 1:1000) and intracellular a-synuclein (Cell Signaling, 1:250) on 4e6 serial sections through the SN (every 6th) [10,30]. Sections were rinsed in phosphate-buffered saline, then blocked in normal donkey serum (10%) before incubating overnight in primary antibodies.…”

Section: Immunofluorescent Stainingmentioning

confidence: 99%

“…The intrastriatal 6-OHDA creates a slow nigrostriatal lesion due to the retrograde transport of the toxin from striatum to SN-DA cell bodies [29]. The use of this double lesion model has been shown by our group and others to better mimic the behavioral and pathological changes associated with PD, including motor deficits, a loss of SN-DA and LC-NE tyrosine hydroxylase (TH)-positive cells, increased asynuclein expression, reduced BDNF expression, and increased neuroinflammation [10,26,30]. We hypothesized for the current study that biomimetic, high-frequency VNS more closely resembling LC neuronal properties, would be ideal for upregulating the LC-NE system, consequentially reducing neuroinflammation and motor deficits.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

et al. 2020

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Background: Vagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the solitary nucleus. Degeneration of the LC in Parkinson's disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify disease progression. We previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss. Objective: The goal of this study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model. Methods: Eleven days after DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, noradrenergic lesion, administered systemically)/6-OHDA (6-hydroxydopamine, dopaminergic lesion, administered intrastriatally) rats were implanted with VNS devices, and received either low-frequency VNS, standardfrequency VNS, or high-frequency microburst VNS. After 10 days of treatment and behavioral assessment, rats were euthanized, right prefrontal cortex (PFC) was dissected for norepinephrine assessment, and the left striatum, bilateral substantia nigra (SN), and LC were sectioned for immunohistochemical detection of catecholamine neurons, a-synuclein, astrocytes, and microglia.Results: At higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC.Additionally, higher VNS frequencies resulted in lower intrasomal a-synuclein accumulation and glial density in the SN. Conclusions: These data indicate that higher stimulation frequencies provided the greatest attenuation of behavioral and pathological markers in this PD model, indicating therapeutic potential for these VNS paradigms.

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BDNF alleviates Parkinson's disease by promoting STAT3 phosphorylation and regulating neuronal autophagy

Geng

Zou

et al. 2023

Cell Tissue Res

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual death of dopaminergic neurons. Brain-derived neurotrophic factor (BDNF) and its receptors are widely distributed throughout the central nervous system, which can promote the survival and growth of neurons and protect neurons. This study revealed that BDNF promotes STAT3 phosphorylation and regulates autophagy in neurons. The PD mouse model was established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, SH-SY5Y cells were treated with 1-methyl-4-phenyl-pyridinium (MPP+) to establish a PD cell model. The level of BDNF was low in PD model mice and SH-SY5Y cells treated with MPP+. BDNF enhanced the levels of p-TrkB, P-STAT3, PINK1, and DJ-1. BDNF promoted autophagy, inhibited the level of p-α-syn (Ser129) and enhanced cell proliferation. The autophagy inhibitor 3-Methyladenine (3-methyladenine, 3-MA) reversed the protective effects of BDNF on neurons. BiFC assay results showed that there was a direct physical interaction between BDNF and STAT3, and coimmunoprecipitation experiments indicated an interaction between STAT3 and PI3K. The PI3K agonist Recilisib activated the PI3K/AKT/mTOR pathway, promoted autophagy, and alleviated neuronal cell damage. BDNF alleviates PD pathology by promoting STAT3 phosphorylation and regulating neuronal autophagy in SH-SY5Y cells and cultured primary neurons. Finally, BDNF has neuroprotective effects on PD model mice.

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Effects of vagus nerve stimulation are mediated in part by TrkB in a parkinson’s disease model

Cited by 17 publications

References 61 publications

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke

Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

BDNF alleviates Parkinson's disease by promoting STAT3 phosphorylation and regulating neuronal autophagy

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