5‐HT<sub>1F</sub> receptor‐mediated mitochondrial biogenesis for the treatment of Parkinson's disease

Scholpa, Natalie E.; Lynn, Mary K.; Corum, Daniel; Boger, Heather A.; Schnellmann, Rick G.

doi:10.1111/bph.14076

Cited by 37 publications

(39 citation statements)

References 59 publications

(70 reference statements)

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“…Moreover, LY344864 enhanced the recovery of renal function in an animal model of acute kidney injury by increasing mitochondrial biogenesis [117]. In other studies, LY344864 enhanced mitochondrial homeostasis in control and in 6hydroxydopamine lesioned mice, and increased locomotor activity in the lesioned mice [118]. These data suggest mitochondrial dysfunction could have a role in migraine pathophysiology, and that perhaps 5-HT 1F receptor activity could help offset this dysfunction.…”

Section: A Role For Mitochondria?mentioning

confidence: 76%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second-and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT 1B/1D receptors. The discovery that the serotonin 1F (5-HT 1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT 1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT 1B receptors, the activation of 5-HT 1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT 1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT 1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT 1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT 1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT 1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT 1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT 1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

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Section: A Role For Mitochondria?mentioning

confidence: 76%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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“…Mitochondrial dysfunction plays an important role in the progression of PD (Burbulla et al, ; Scholpa, Lynn, Corum, Boger, & Schnellmann, ). Damaged mitochondria can negatively affect the physiological functions of neurons.…”

Section: Discussionmentioning

confidence: 99%

Roflupram exerts neuroprotection via activation of CREB/PGC‐1α signalling in experimental models of Parkinson's disease

Zhong

Dong

Qin

et al. 2020

British J Pharmacology

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Background and Purpose:Roflupram improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of roflupram on Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD. Experimental Approach:We used an in vitro PD model of SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP + ). Cell viability and apoptosis were analysed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity, and ROS were measured by a mitochondrial tracker, Seahorse Analyzer, and a MitoSOX-Red dye. For in vivo PD model, behavioural tests, Nissl staining, and immunohistochemistry were used to evaluate protection by roflupram. The levels of TH, cAMP response element-binding protein (CREB), and PPARγ coactivator-1α (PGC-1α) were analysed by western blotting. Key Results: Roflupram decreased MPP + -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. Roflupram also increased mitochondrial respiratory capacity, decreased ROS production, and restored mitochondrial morphology. Roflupram reversed the MPP + -induced reductions of phosphorylated CREB, PGC-1α and TH. These protective effects were blocked by the PKA inhibitor H-89 or by PGC-1α siRNA. In mice treated with MPTP, roflupram significantly improved motor functions. Roflupram prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum. Conclusion and Implications: Roflupram protected dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, roflupram has potential as a protective drug in the treatment of PD.Abbreviations: CREB, cAMP response element-binding protein; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; MMP, mitochondrial membrane potential; MPP + , 1-methyl-4-phenylpyridinium iodide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OCR, oxygen consumption rate; PD, Parkinson's disease; PGC-1α, PPARγ coactivator-1α; SN, substantia nigra; TMRE, tetramethylrhodamine ethyl ester perchlorate.Jiahong Zhong and Wenli Dong have equal contribution to this work.

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“…As one of the most common neurodegenerative disorders, the incidence of Parkinson’s disease (PD) affects up to 1% of the global population over 50 years of age [ 1 , 2 , 3 ]. PD patients often suffer from progressive cognitive and motor deficits, such as tremors, bradykinesia and rigidity, primarily due to dopaminergic neuron degeneration in the substantia nigra (SN) and dopamine (DA) depletion in the striatum [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a lipophilic compound, selectively damages neurons in the nigrostriatal dopaminergic pathway and causes Parkinsonism. The C57BL/6 mouse strain is known to be highly susceptible to this neurotoxin, and MPTP-treated mice have been widely used as an in vivo model to test therapeutic strategies in PD [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Preparation and Neuroprotective Activity of Glucuronomannan Oligosaccharides in an MPTP-Induced Parkinson’s Model

et al. 2020

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Parkinson’s disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice.

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5‐HT_1F receptor‐mediated mitochondrial biogenesis for the treatment of Parkinson's disease

Abstract: These data revealed that LY344864-induced MB attenuates dopaminergic neuron loss and improves behavioural endpoints in this model. We suggest that stimulating MB may be beneficial for the treatment of Parkinson's disease and that the 5-HT receptor may be an effective therapeutic target.

Cited by 37 publications

References 59 publications

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Roflupram exerts neuroprotection via activation of CREB/PGC‐1α signalling in experimental models of Parkinson's disease

Preparation and Neuroprotective Activity of Glucuronomannan Oligosaccharides in an MPTP-Induced Parkinson’s Model

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5‐HT1F receptor‐mediated mitochondrial biogenesis for the treatment of Parkinson's disease

Abstract: These data revealed that LY344864-induced MB attenuates dopaminergic neuron loss and improves behavioural endpoints in this model. We suggest that stimulating MB may be beneficial for the treatment of Parkinson's disease and that the 5-HT receptor may be an effective therapeutic target.

Cited by 37 publications

References 59 publications

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Roflupram exerts neuroprotection via activation of CREB/PGC‐1α signalling in experimental models of Parkinson's disease

Preparation and Neuroprotective Activity of Glucuronomannan Oligosaccharides in an MPTP-Induced Parkinson’s Model

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5‐HT_1F receptor‐mediated mitochondrial biogenesis for the treatment of Parkinson's disease