scholarly journals Magnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah-Anna Hescham ◽  
Po-Han Chiang ◽  
Danijela Gregurec ◽  
Junsang Moon ◽  
Michael G. Christiansen ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Motor Behavior ◽  
Receptor Potential ◽  
Motor Deficits ◽  
Subcortical Structures ◽  
Hardware Failure ◽  
Implanted Electrodes ◽  
Therapeutic Benefits ◽  
6 Hydroxydopamine ◽  
Deep Brain

AbstractDeep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson’s disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.

scholarly journals Acrolein scavenger dimercaprol offers neuroprotection in an animal model of Parkinson’s disease: implication of acrolein and TRPA1

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Liangqin Shi ◽  
Yazhou Lin ◽  
Yucheng Jiao ◽  
Seth A. Herr ◽  
Jonathan Tang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Critical Factor ◽  
Receptor Potential ◽  
Motor Deficits ◽  
Neuron Death ◽  
6 Hydroxydopamine

Abstract Background The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson’s disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits. Methods DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein. Results DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein’s ability to upregulate TRPA1 was also verified in vitro using cell lines. Conclusions These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.

scholarly journals Neuroprotective and Symptomatic Effects of Cannabidiol in an Animal Model of Parkinson’s Disease

2021 ◽  
Vol 22 (16) ◽  
pp. 8920
Author(s):  
Claudio Giuliano ◽  
Miriam Francavilla ◽  
Gerardo Ongari ◽  
Alessandro Petese ◽  
Cristina Ghezzi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transient Receptor Potential ◽  
Cannabis Sativa ◽  
Neurodegenerative Disorder ◽  
Receptor Potential ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Transient Receptor Potential Vanilloid ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.

scholarly journals Endocannabinoids in the gastrointestinal tract

2016 ◽  
Vol 311 (4) ◽  
pp. G655-G666 ◽  
Author(s):  
Yunna Lee ◽  
Jeongbin Jo ◽  
Hae Young Chung ◽  
Charalabos Pothoulakis ◽  
Eunok Im
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Gastrointestinal Diseases ◽  
Transient Receptor Potential Channels ◽  
Therapeutic Benefits ◽  
Potential Channels ◽  
Transient Receptor

The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs, have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation, and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.

scholarly journals TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258911
Author(s):  
Takatoshi Uchida ◽  
Shota Shimizu ◽  
Reiko Yamagishi ◽  
Suzumi M. Tokuoka ◽  
Yoshihiro Kita ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Intraocular Pressure ◽  
Mechanical Stimulation ◽  
Trabecular Meshwork ◽  
Cellular Response ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Stretch ◽  
Therapeutic Benefits ◽  
Aqueous Outflow

Trabecular meshwork constitutes the conventional outflow pathway and controls intraocular pressure by regulating aqueous outflow. Mechanical stimulation has been studied as one of the triggers to regulate aqueous outflow in trabecular meshwork, but it is not well understood. We investigated that how transient receptor potential cation channel subfamily V member 4 (TRPV4) functions in human trabecular meshwork cells (HTMC) and affects intraocular pressure (IOP). HTMC were treated with TRPV4 siRNA, followed by incubation for 24 hours. We confirmed the suppression of TRPV4 mRNA expression and the reduction of Ca2+ influx by the TRPV4 agonist GSK1016790A in TRPV4 siRNA-treated HTMC. TRPV4 siRNA-treated HTMC exhibited a significant reduction in Ca2+ influx and production of arachidonic acid and prostaglandin (PG) E2 induced by mechanical stretch, and direct activation of TRPV4 by GSK1016790A increased production of arachidonic acid, PGE2, and PGD2 and inhibited gel contraction. Furthermore, TRPV4-deficient mice had higher IOP than wild-type mice, and GSK1016790A administration lowered IOP. These results suggest that TRPV4 mediates the cellular response induced by trabecular meshwork stretch, leading to IOP reduction through the production of prostaglandins and inhibition of cell contraction. Targeting TRPV4 may have therapeutic benefits that lead to lowering IOP in glaucoma patients.

scholarly journals Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

2013 ◽  
Vol 305 (9) ◽  
pp. R1040-R1050 ◽  
Author(s):  
Viktor V. Feketa ◽  
Adithya Balasubramanian ◽  
Christopher M. Flores ◽  
Mark R. Player ◽  
Sean P. Marrelli
Keyword(s):  
Core Temperature ◽  
Muscle Activity ◽  
Transient Receptor Potential ◽  
Abdominal Cavity ◽  
Receptor Potential ◽  
Wireless Transmitters ◽  
Implanted Electrodes ◽  
External Cooling ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Mild decrease of core temperature (32–34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 ± 1.8; compound 5: 23.8 ± 2.0; TRPM8 KO: 19.7 ± 1.9 V·s/min), tachycardia (ΔHR = 124 ± 31; 121 ± 13; 121 ± 31 beats/min) and drop in core temperature (−3.6 ± 0.1; −3.4 ± 0.4; −3.6 ± 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 ± 3.0 vs. DHC: 5.1 ± 2.0 V·s/min), tachycardia (ΔHR = 204 ± 25 vs. 3 ± 35 beats/min) and produced a profound drop in core temperature (−2.2 ± 0.6 vs. −8.9 ± 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia.

scholarly journals Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Maurício dos Santos Pereira ◽  
Gabriel Henrique Dias Abreu ◽  
Jeremy Rocca ◽  
Sabah Hamadat ◽  
Rita Raisman-Vozari ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Dorsal Striatum ◽  
Receptor Potential ◽  
Neuronal Cultures ◽  
Transient Receptor Potential Vanilloid ◽  
Tnf Α ◽  
Activated State ◽  
Transient Receptor ◽  
6 Hydroxydopamine ◽  
Factor Α

Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.

scholarly journals Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

2021 ◽  
Author(s):  
Albert Misko ◽  
Laura D Weinstock ◽  
Sitara B Sankar ◽  
Amanda Furness ◽  
Yulia Grishchuk ◽  
...  
Keyword(s):  
Motor Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Brief Assessment ◽  
Blood Cytokines ◽  
Mucolipidosis Iv ◽  
Transient Receptor

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss-of-function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.

scholarly journals Changes in motor behavior, neuropathology, and gut microbiota of a Batten disease mouse model following administration of acidified drinking water

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tyler B. Johnson ◽  
Logan M. Langin ◽  
Jing Zhao ◽  
Jill M. Weimer ◽  
David A. Pearce ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Motor Behavior ◽  
Neurodegenerative Disorder ◽  
Tap Water ◽  
Batten Disease ◽  
Motor Deficits ◽  
Therapeutic Benefits ◽  
Water Ph

Abstract CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease. The Cln3−/− mouse model displays characteristic features of the human disease including motor deficits. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3−/− mice normalized to control levels, indicating a disease-modifying effect of acidified water. Here we investigated if acidified water administered from postnatal day 21 has therapeutic benefits in Cln3−/− mice. Indeed, acidified water temporarily attenuated the motor deficits, had beneficial effects on behavioral parameters and prevented microglial activation in the brain of Cln3−/− mice. Interestingly, in control mice, acidified drinking water caused brain region-specific glial activation and significant changes in motor performance. Since the gut microbiota can influence neurological functions, we examined it in our disease model and found that the gut microbiota of Cln3−/− mice was markedly different from control mice, and acidified water differentially changed the gut microbiota composition in these mice. These results indicate that acidified water may provide therapeutic benefit to CLN3 Batten disease patients, and that the pH of drinking water is a major environmental factor that strongly influences the results of murine behavioral and pathological studies.

Inositol lipids and TRPC channel activation

2007 ◽  
Vol 74 ◽  
pp. 37-45 ◽  
Author(s):  
James W. Putney
Keyword(s):  
Plasma Membrane ◽  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Calcium Signalling ◽  
Receptor Potential ◽  
Breakdown Product ◽  
Channel Activation ◽  
Inositol Lipids ◽  
Transient Receptor ◽  
Secondary Mechanism

The original hypothesis put forth by Bob Michell in his seminal 1975 review held that inositol lipid breakdown was involved in the activation of plasma membrane calcium channels or ‘gates’. Subsequently, it was demonstrated that while the interposition of inositol lipid breakdown upstream of calcium signalling was correct, it was predominantly the release of Ca2+ that was activated, through the formation of Ins(1,4,5)P3. Ca2+ entry across the plasma membrane involved a secondary mechanism signalled in an unknown manner by depletion of intracellular Ca2+ stores. In recent years, however, additional non-store-operated mechanisms for Ca2+ entry have emerged. In many instances, these pathways involve homologues of the Drosophila trp (transient receptor potential) gene. In mammalian systems there are seven members of the TRP superfamily, designated TRPC1–TRPC7, which appear to be reasonably close structural and functional homologues of Drosophila TRP. Although these channels can sometimes function as store-operated channels, in the majority of instances they function as channels more directly linked to phospholipase C activity. Three members of this family, TRPC3, 6 and 7, are activated by the phosphoinositide breakdown product, diacylglycerol. Two others, TRPC4 and 5, are also activated as a consequence of phospholipase C activity, although the precise substrate or product molecules involved are still unclear. Thus the TRPCs represent a family of ion channels that are directly activated by inositol lipid breakdown, confirming Bob Michell's original prediction 30 years ago.

Sign in / Sign up

Export Citation Format

Share Document