Global pollination is threatened by declining insect pollinator populations that may be linked to neonicotinoid pesticide use. Neonicotinoids over stimulate neurons and depolarize their mitochondria, ...producing immobility and death. However, mitochondrial function can be improved by near infrared light absorbed by cytochrome c oxidase in mitochondrial respiration. In flies, daily exposure to 670nm light throughout life increases average lifespan and aged mobility, and reduces systemic inflammation. Here we treat bumble bees with Imidacloprid a common neonicotinoid. This undermined ATP and rapidly induced immobility and reduced visual function and survival. Bees exposed to insecticide and daily to 670nm light showed corrected ATP levels and significantly improved mobility allowing them to feed. Physiological recordings from eyes revealed that light exposure corrected deficits induced by the pesticide. Overall, death rates in bees exposed to insecticide but also given 670nm light were indistinguishable from controls. When Imidacloprid and light exposure were withdrawn, survival was maintained. Bees and insects generally cannot see deep red light so it does not disturb their behaviour. Hence, we show that deep red light exposure that improves mitochondrial function, reverses the sensory and motor deficits induced by Imidacloprid. These results may have important implications as light delivery is economic and can be placed in hives/colonies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This review highlights recent findings that describ how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between ...P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence tear secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma. Purines act at receptors on both the trabecular meshwork and ciliary epithelium to modulate intraocular pressure (IOP); ATP-release pathways of inflow and outflow cells differ, possibly permitting differential modulation of adenosine delivery. Modulators of trabecular meshwork cell ATP release include cell volume, stretch, extracellular Ca2+ concentration, oxidation state, actin remodeling and possibly endogenous cardiotonic steroids. In the lens, osmotic stress leads to ATP release following TRPV4 activation upstream of hemichannel opening. In the anterior eye, diadenosine polyphosphates such as Ap4A act at P2 receptors to modulate the rate and composition of tear secretion, impact corneal wound healing and lower IOP. The Gq11-coupled P2Y1-receptor contributes to volume control in Müller cells and thus the retina. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the demise of retinal ganglion cells. In RPE cells, the balance between extracellular ATP and adenosine may modulate lysosomal pH and the rate of lipofuscin formation. In optic nerve head astrocytes, mechanosensitive ATP release via pannexin hemichannels, coupled with stretch-dependent upregulation of pannexins, provides a mechanism for ATP signaling in chronic glaucoma. With so many receptors linked to divergent functions throughout the eye, ensuring the transmitters remain local and stimulation is restricted to the intended target may be a key issue in understanding how physiological signaling becomes pathological in ocular disease.
Display omitted
•Recent findings in purinergic signaling of the anterior and posterior eye.•ATP release mechanisms, receptor interactions and signaling pathways.•Physiological and pathophysiological implications for ocular function and vision.
Mitochondria play a major role in aging. Over time, mutations accumulate in mitochondrial DNA leading to reduced adenosine triphosphate (ATP) production and increased production of damaging reactive ...oxygen species. If cells fail to cope, they die. Reduced ATP will result in declining cellular membrane potentials leading to reduced central nervous system function. However, aged mitochondrial function is improved by long wavelength light (670 nm) absorbed by cytochrome c oxidase in mitochondrial respiration. In Drosophila, lifelong 670-nm exposure extends lifespan and improves aged mobility. Here, we ask if improved mitochondrial metabolism can reduce functional senescence in metabolism, sensory, locomotor, and cognitive abilities in old flies exposed to 670 nm daily for 1 week. Exposure significantly increased cytochrome c oxidase activity, whole body energy storage, ATP and mitochondrial DNA content, and reduced reactive oxygen species. Retinal function and memory were also significantly improved to levels found in 2-week-old flies. Mobility improved by 60%. The mode of action is likely related to improved energy homeostasis increasing ATP availability for ionic ATPases critical for maintenance of neuronal membrane potentials. 670-nm light exposure may be a simple route for resolving problems of aging.
Background and Purpose
As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu2/mGlu3) receptor ...activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu2 component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu3.
Experimental Approach
The somatosensory ventrobasal thalamus (VB) is an established model for probing fundamental principles of thalamic function. In vitro slices conserving VB–TRN circuitry from wild‐type and mGlu3 knockout mouse brains were used to record IPSPs and mIPSCs. In vivo extracellular recordings were made from VB neurons in anaesthetised rats. A range of selective pharmacological agents were used to probe Group II mGlu receptor function (agonist, LY354740; antagonist, LY341495; mGlu2 positive allosteric modulator, LY487379 and mixed mGlu2 agonist/mGlu3 antagonist LY395756).
Key Results
The in vitro and in vivo data are complementary and suggest that mGlu3 receptor activation is largely responsible for potentiating responses to somatosensory stimulation by reducing inhibition from the TRN.
Conclusions and Implications
mGlu3 receptor activation in the VB likely enables important somatosensory information to be discerned from background activity. These mGlu3 receptors are likely to be endogenously activated via ‘glutamate spillover’. In cognitive thalamic nuclei, this mechanism may be of importance in governing attentional processes. Positive allosteric modulation of endogenous mGlu3 receptor activation may therefore enhance cognitive function in pathophysiological disease states, such as schizophrenia, thus representing a highly specific therapeutic target.
LINKED ARTICLES
This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc
Targeting amyloid-β in glaucoma treatment Guo, Li; Salt, Thomas E; Luong, Vy ...
Proceedings of the National Academy of Sciences,
08/2007, Letnik:
104, Številka:
33
Journal Article
Recenzirano
Odprti dostop
The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-β (Aβ) deposition, neuronal apoptosis, and cell loss. Here, we provide ...evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that Aβ colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner. We demonstrate that targeting different components of the Aβ formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the Aβ pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the Aβ pathway may be the most effective strategy in Aβ-related diseases.
Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence ...suggests that both compounds can affect brain function and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the in vitro and in vivo effects produced by xanthurenic acid appear to be mediated by the activation of mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders.
This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.
•Cinnabarinic and xanthurenic acids (CA, XA) are neuroactive kynurenines metabolites.•CA acts as an orthosteric agonist of mGlu4 receptors.•Some in vitro and in vivo effects of XA are mediated by mGlu2/3 receptors.•Other targets of CA and XA include the Ah receptor and VGLUT, respectively.•CA and XA might have a role in the pathophysiology of CNS disorders.
Here in-vivo retinal imaging (optical coherence tomography) and electrophysiology measures indicate that the inner retina exhibits thinning of retinal ganglion cell axons and dysfunction of these ...neurons prior to outer retinal changes in a 5 × FAD transgenic mouse model (Lim et al.). In the current study, they find that the chromatic pupillary response (a functional measure of melanopsin retinal ganglion cells) exhibited higher variability in mild-moderate Alzheimer's disease patients but were not significantly separated from controls (n = 26/group), whereas the rod mediated transient pupillary light response was altered. Using laser scanning in-vivo confocal microscopy they found morphological differences including a larger dendritic cell field area and perimeter in patients with mild cognitive impairment compared to controls. Cao et al. found in 40 recent small subcortical infarct patients vs. 46 controls that optical coherence tomography angiography was reduced in the macula area (both superficial and deep retinal capillary plexus) and around the optic nerve head (radial peripapillary capillary bed) which correlated with peripapillary retinal nerve fiber layer thickness.
In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, ...independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. These mechanisms and their potential treatment include excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation and neurotrophin deprivation. All of these mechanisms ultimately lead to programmed cell death with loss of RGCs. In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic.
► Neuroprotection is currently a controversial area in glaucoma, even though it is recognized that there is a need an alternative therapeutic approach, independent of IOP reduction. ► Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. ► In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic.
The thalamus plays a pivotal role in the integration and processing of sensory, motor, and cognitive information. It is therefore important to understand how the thalamus operates in states of both ...health and disease. In the present review, we discuss the function of the Group II metabotropic glutamate (mGlu) receptors within thalamic circuitry, and how they may represent therapeutic targets in treating disease states associated with thalamic dysfunction.
Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate ...cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies. The NMDA receptor blocker phencyclidine (PCP), known to evoke certain schizophrenia-like symptoms in humans, elevated the power of beta oscillations in ACC and caused a shift in oscillation frequency from the gamma range to the beta range. These enhanced beta oscillations were reduced by the Group II mGlu receptor agonists. These results show that Group II mGlu receptors, and specifically mGlu2, modulate network oscillations. Furthermore, attenuation of the effect of PCP suggests that mGlu2 receptors may stabilise aberrant network activity. These results underline the importance of Group II mGlu receptors, and particularly mGlu2, as targets for the treatment of neuropsychiatric and neurodegenerative diseases.
•Rat anterior cingulate cortex shows kainate-induced beta and gamma frequency oscillations in vitro.•Group II metabotropic glutamate (mGlu2 and mGlu3) receptors modulate these oscillations.•The NMDA antagonist phencyclidine (PCP) induces a significant increase in beta frequency oscillations.•The PCP effect is attenuated by activation of mGlu2 receptors.
PDF
