2010;17(14):1430C1449. of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. Conclusion: The aim of this review is usually to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases. extracts, resveratrol, fish oil and -3 (n-3) fatty acids, stem cells, as well as neurotrophic factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF) [25-34]. To this list other natural compounds can be added, namely phytocannabinoids (pCBs) and endogenous cannabinoids (eCBs), based on impartial studies that documented their neuroprotective effects in ocular tissues [35-44]. In this review, we summarize the main outcomes of preclinical studies that support the potential benefits of pCBs and eCBs as new neuroprotective agents, potentially useful to prevent, slow down or even cure glaucoma and retinal neurodegenerative diseases. 2.?PHYTOCANNABINOIDS AND ENDOCANNABINOIDS: SYNTHESIS AND PRODUCTION The pCBs family is best represented by the active ingredient of cannabis (or Flom 1975Purnell and Gregg, 1975Cooler and Gregg 1977Flach 2002Tomida 2006Cat, RatEyeIOP reductionGlaucomaColasanti 1990MouseAnterior EyeIOP reductionGlaucomaCaldwell 2013DogEyeIOP reductionGlaucomaFischer 2013RabbitCorneaIOP reductionGlaucomaHingorani 2012RatRetinal Ganglion CellsCell protectionGlaucomaEl-Remessy 2003 Crandall 2007RatRetinal Neuronal CellsCell protectionDiabetic Myricitrin (Myricitrine) retinopathyEl-Remessy 2006ChickRetinal SectionCell protectionDiabetic retinopathy and glaucomaAraujoa 2017 Open in a separate window 5.?ENDOCANNABINOIDS AND RETINAL PROTECTION eCBs show neuroprotective effects in different models of retinal neurodegeneration [35, 37-39,110]. Retinal ischemia models, induced by chemicals or acute elevation of IOP, affect the viability of a variety of amacrine, rod bipolar and RGC cells and lead to increased glutamate levels and activation of ionotropic glutamate (NMDA and AMPA) receptors. Consequently, intracellular calcium ions and NOS activity increase, resulting in glutamate-mediated excitotoxic retinal cell death [116, 117]. In that context, AEA produces a neuroprotective effect against retinal cell Myricitrin (Myricitrine) death induced by high IOP, through engagement of CB1 and TRPV1 [35]. In particular, blocking AEA degradation with the specific FAAH inhibitor URB587, or mimicking this effect by using the non-hydrolysable analogue of AEA, methanandamide, confers retinal neuroprotection against high IOP-induced cell death [35]. Moreover, CB1 was reported to reduce IOP the -adrenergic system, through inhibition of norepinephrine release [118]. In a rat model of optic nerve axotomy, URB587 promotes retinal ganglion cell neuroprotection through CB1, and its efficacy declines with age and is associated to a significant increase in AEA levels. In parallel, a decrease in the AEA congener a mechanism involving CB1 and the PI3K/Akt and/or MEK/ERK1/2 signaling pathways [110]. Otherwise it has been shown that deletion of CB1 or treatment of diabetic mice with CB1 antagonist SR141716 prevented retinal cell death in a mouse model of DR, as well as in human primary retinal endothelial cells (HREC) exposed to high glucose, by reducing MAPK activation, oxidative stress and inflammatory signaling [119]. Also oral PEA given for three months seems to reduce IOP in ocular hypertensive patients [120], possibly by increasing AEA content, that is reduced in glaucomatous eyes [99], through inhibition of its degradation [121]. 2-AG was found to lower IOP in a concentration- and CB1-dependent manner [122, 123], and indeed in a murine model of disease MAGL blockade can lower IOP by raising endogenous eCB levels [123] and consequently providing indirect neuroprotection. Interestingly, several studies reported that TRPV1 plays a major role as a mediator of RGC function and survival [124-126]. In line with this, in an inducible mouse model of glaucoma both genetic (knock-outs) and pharmacological (antagonists) blockade of TRPV1 accelerate RGC degeneration upon exposure to elevated IOP [125]. Moreover, TRPV1 expression increases in monkey and human RGCs in response to elevated IOP, thus supporting enhanced excitability. Such an enhancement Myricitrin (Myricitrine) is likely mediated by Ca2+ currents, since activation of TRPV1 in RGCs increases intracellular Ca2+ in isolated RGCs [124, 126]. In addition to.Based Complement. Results: Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. Conclusion: The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases. extracts, resveratrol, fish oil and -3 (n-3) fatty acids, stem cells, as well as neurotrophic factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF) [25-34]. To this list other natural compounds can be added, namely phytocannabinoids (pCBs) and endogenous cannabinoids (eCBs), based on independent studies that documented their neuroprotective effects in ocular tissues [35-44]. In this review, we summarize the main outcomes of preclinical studies that support the potential benefits of pCBs and eCBs as new neuroprotective agents, potentially useful to prevent, slow down or even cure glaucoma and retinal neurodegenerative diseases. 2.?PHYTOCANNABINOIDS AND ENDOCANNABINOIDS: SYNTHESIS AND PRODUCTION The pCBs family is best represented by the active ingredient of cannabis (or Flom 1975Purnell and Gregg, 1975Cooler and Gregg 1977Flach 2002Tomida 2006Cat, RatEyeIOP reductionGlaucomaColasanti 1990MouseAnterior EyeIOP reductionGlaucomaCaldwell 2013DogEyeIOP reductionGlaucomaFischer 2013RabbitCorneaIOP reductionGlaucomaHingorani 2012RatRetinal Ganglion CellsCell protectionGlaucomaEl-Remessy 2003 Crandall 2007RatRetinal Neuronal CellsCell protectionDiabetic retinopathyEl-Remessy 2006ChickRetinal SectionCell protectionDiabetic retinopathy and glaucomaAraujoa 2017 Open in a separate window 5.?ENDOCANNABINOIDS AND RETINAL PROTECTION eCBs show neuroprotective effects in different models of retinal neurodegeneration [35, 37-39,110]. Retinal ischemia models, induced by chemicals or acute elevation of IOP, affect the viability of a variety of amacrine, rod bipolar and RGC cells and lead to increased glutamate levels and activation of ionotropic glutamate (NMDA and AMPA) receptors. Consequently, intracellular calcium ions and NOS activity increase, resulting in glutamate-mediated excitotoxic retinal cell death [116, 117]. In that context, AEA produces a neuroprotective effect against retinal cell death induced by high IOP, through engagement of CB1 and TRPV1 [35]. In particular, blocking AEA degradation with the specific FAAH inhibitor URB587, or mimicking this effect by using the non-hydrolysable analogue of AEA, methanandamide, confers retinal neuroprotection against high IOP-induced cell death [35]. Moreover, CB1 was reported to reduce IOP the -adrenergic system, through inhibition of norepinephrine release [118]. In a rat model of optic nerve axotomy, URB587 promotes retinal ganglion cell neuroprotection through CB1, and its efficacy declines with age and is associated to a significant increase in AEA levels. In parallel, a decrease in the AEA congener a mechanism involving CB1 and the PI3K/Akt and/or MEK/ERK1/2 signaling pathways [110]. Otherwise it has been shown that deletion of CB1 or treatment of diabetic mice with CB1 antagonist SR141716 prevented retinal cell death in a mouse model of DR, as well as in human primary retinal endothelial cells (HREC) exposed to high glucose, by reducing MAPK activation, oxidative stress and inflammatory signaling [119]. Also oral PEA given for three months seems to reduce IOP in ocular hypertensive patients [120], possibly by increasing AEA content, that is reduced in glaucomatous eyes [99], through inhibition of its degradation [121]. 2-AG was found to lower IOP in a concentration- and CB1-dependent manner [122, 123], and indeed in a murine model of disease MAGL blockade can lower IOP by raising endogenous eCB levels [123] and consequently providing indirect neuroprotection. Interestingly, several studies reported.2009;50(2):717C728. to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain. Results: Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. Conclusion: The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as fresh neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases. extracts, resveratrol, fish oil and -3 (n-3) fatty acids, stem cells, as well as neurotrophic factors such as brain-derived neurotrophic element (BDNF), ciliary neurotrophic element (CNTF), glial cell-line derived neurotrophic element (GDNF) and nerve growth element (NGF) [25-34]. To this list other natural compounds can be added, namely phytocannabinoids (pCBs) and endogenous cannabinoids (eCBs), based on self-employed studies that recorded their neuroprotective effects in ocular cells [35-44]. With this review, we summarize the main results of preclinical studies that support the potential benefits of pCBs and eCBs as fresh neuroprotective agents, potentially useful to prevent, slow down or even remedy glaucoma and retinal neurodegenerative diseases. 2.?PHYTOCANNABINOIDS AND ENDOCANNABINOIDS: SYNTHESIS AND PRODUCTION The pCBs family is best represented from the active ingredient of cannabis (or Flom 1975Purnell and Gregg, 1975Cooler and Gregg 1977Flach 2002Tomida 2006Cat, RatEyeIOP reductionGlaucomaColasanti 1990MouseAnterior EyeIOP reductionGlaucomaCaldwell 2013DogEyeIOP reductionGlaucomaFischer 2013RabbitCorneaIOP reductionGlaucomaHingorani 2012RatRetinal Ganglion CellsCell protectionGlaucomaEl-Remessy 2003 Crandall 2007RatRetinal Neuronal CellsCell protectionDiabetic retinopathyEl-Remessy 2006ChickRetinal SectionCell protectionDiabetic retinopathy and glaucomaAraujoa 2017 Open in a separate windows 5.?ENDOCANNABINOIDS AND RETINAL Safety eCBs display neuroprotective effects in different models of retinal neurodegeneration [35, 37-39,110]. Retinal ischemia models, induced by chemicals or acute elevation of IOP, impact the viability of a variety of amacrine, pole bipolar and RGC cells and lead to increased glutamate levels and activation of ionotropic glutamate (NMDA and AMPA) receptors. As a result, intracellular calcium ions and NOS activity increase, resulting in glutamate-mediated excitotoxic retinal cell death [116, 117]. In Rabbit Polyclonal to SAA4 that context, AEA generates a neuroprotective effect against retinal cell death induced by high IOP, through engagement of CB1 and TRPV1 [35]. In particular, obstructing AEA degradation with the specific FAAH inhibitor URB587, or mimicking this effect by using the non-hydrolysable analogue of AEA, methanandamide, confers retinal neuroprotection against high IOP-induced cell death [35]. Moreover, CB1 was reported to reduce IOP the -adrenergic system, through inhibition of norepinephrine launch [118]. Inside a rat model of optic nerve axotomy, URB587 promotes retinal ganglion cell neuroprotection through CB1, and its effectiveness declines with age and is connected to a significant increase in AEA levels. In parallel, a decrease in the AEA congener a mechanism involving CB1 and the PI3K/Akt and/or MEK/ERK1/2 signaling pathways [110]. Normally it has been demonstrated that deletion of CB1 or treatment of diabetic mice with CB1 antagonist SR141716 prevented retinal cell death inside a mouse model of DR, as well as in human being main retinal endothelial cells (HREC) exposed to high glucose, by reducing MAPK activation, oxidative stress and inflammatory signaling [119]. Also oral PEA given for three months seems to reduce IOP in ocular hypertensive individuals [120], probably by increasing AEA content, that is reduced in glaucomatous eyes [99], through inhibition of its degradation [121]. 2-AG was found to lower IOP inside a concentration- and CB1-dependent manner [122, 123], and indeed inside a murine model of disease MAGL blockade can lower IOP by raising endogenous eCB levels [123] and consequently providing indirect neuroprotection. Interestingly, several studies reported that TRPV1 takes on a major part like a mediator of RGC function and survival [124-126]. In line with this, in an inducible mouse model of glaucoma both genetic (knock-outs) and pharmacological (antagonists) blockade of TRPV1 accelerate RGC degeneration upon exposure to elevated IOP [125]. Moreover, TRPV1 expression raises in monkey and human being RGCs in response to elevated IOP, thus assisting enhanced excitability. Such an enhancement is likely mediated by Ca2+ currents, since activation of TRPV1 in RGCs raises intracellular Ca2+ in isolated RGCs [124, 126]. In addition to advertising RGC excitability during retinal stress, TRPV1 seems to mediate the release of neuroprotective cytokines, such as interleukin (IL) 6, from glial cells [124]. Instead, in adult retinal explants both genetic and pharmacological blockade of TRPV1 improved RGC survival upon exposure to elevated hydrostatic pressure, as did chelation of extracellular Ca2+ [124]. Activation of TRPV1.[http://dx.doi. The aim of this review is definitely to present a modern look at of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as fresh neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases. extracts, resveratrol, fish oil and -3 (n-3) fatty acids, stem cells, as well as neurotrophic factors such as brain-derived neurotrophic element (BDNF), ciliary neurotrophic element (CNTF), glial cell-line derived neurotrophic element (GDNF) and nerve development aspect (NGF) [25-34]. To the list other organic compounds could be added, specifically phytocannabinoids (pCBs) and endogenous cannabinoids (eCBs), predicated on indie studies that noted their neuroprotective results in ocular tissue [35-44]. Within this review, we summarize the primary final results of preclinical research that support the great things about pCBs and eCBs as brand-new neuroprotective agents, possibly beneficial to prevent, decelerate or even get rid of glaucoma and retinal neurodegenerative illnesses. 2.?PHYTOCANNABINOIDS AND ENDOCANNABINOIDS: SYNTHESIS AND Creation The pCBs family members is most beneficial represented with the active component of cannabis (or Flom 1975Purnell and Gregg, 1975Cooler and Gregg 1977Flach 2002Tomida 2006Cin, RatEyeIOP reductionGlaucomaColasanti 1990MouseAnterior EyeIOP reductionGlaucomaCaldwell 2013DogEyeIOP reductionGlaucomaFischer 2013RabbitCorneaIOP reductionGlaucomaHingorani 2012RatRetinal Ganglion CellsCell protectionGlaucomaEl-Remessy 2003 Crandall 2007RatRetinal Neuronal CellsCell protectionDiabetic retinopathyEl-Remessy 2006ChickRetinal SectionCell protectionDiabetic retinopathy and glaucomaAraujoa 2017 Open up in another home window 5.?ENDOCANNABINOIDS AND RETINAL Security eCBs present neuroprotective effects in various types of retinal neurodegeneration [35, 37-39,110]. Retinal ischemia versions, induced by chemical substances or severe elevation of IOP, influence the viability of a number of amacrine, fishing rod bipolar and RGC cells and result in increased glutamate amounts and activation of ionotropic glutamate (NMDA and AMPA) receptors. Therefore, intracellular calcium mineral ions and NOS activity boost, leading to glutamate-mediated excitotoxic retinal cell loss of life [116, 117]. For the reason that framework, AEA creates a neuroprotective impact against retinal cell loss of life induced by high IOP, through engagement of CB1 and TRPV1 [35]. Specifically, preventing AEA degradation with the precise FAAH inhibitor URB587, or mimicking this impact utilizing the non-hydrolysable analogue of AEA, methanandamide, confers retinal neuroprotection against high IOP-induced cell loss of life [35]. Furthermore, CB1 was reported to lessen IOP the -adrenergic program, through inhibition of norepinephrine discharge [118]. Within a rat style of optic nerve axotomy, URB587 promotes retinal ganglion cell neuroprotection through CB1, and its own efficiency declines with age group and is linked to a substantial upsurge in AEA amounts. In parallel, a reduction in the AEA congener a system involving CB1 as well as the PI3K/Akt and/or MEK/ERK1/2 signaling pathways [110]. In any other case it’s been proven that deletion of CB1 or treatment of diabetic mice with CB1 antagonist SR141716 avoided retinal cell loss of life within a mouse style of DR, aswell as in individual major retinal endothelial cells (HREC) subjected to high blood sugar, by reducing MAPK activation, oxidative tension and inflammatory signaling [119]. Also dental PEA provided for 90 days seems to decrease IOP in ocular hypertensive sufferers [120], perhaps by raising AEA Myricitrin (Myricitrine) content, that’s low in glaucomatous eye [99], through inhibition of its degradation [121]. 2-AG was discovered to lessen IOP within a focus- and CB1-reliant way [122, 123], and in a murine model indeed.Fischer K.M., Ward D.A., Hendrix D.V.H. cascades that modulate peripheral and central cell features. A fine stability between biosynthetic and degrading enzymes that control the proper focus of eCBs provides been shown to supply neuroprotection in distressing, ischemic, inflammatory and neurotoxic harm of the mind. Results: Because the lifestyle of eCBs and their binding receptors was recorded in the retina of several varieties (from fishes to primates), their participation in the visible processing continues to be demonstrated, recently having a concentrate on retinal neurodegeneration and neuroprotection. Summary: The purpose of this review can be to Myricitrin (Myricitrine) provide a modern look at from the endocannabinoid program, to be able to discuss in an improved perspective obtainable data from preclinical research on the usage of eCBs as fresh neuroprotective agents, possibly beneficial to prevent glaucoma and retinal neurodegenerative illnesses. extracts, resveratrol, seafood essential oil and -3 (n-3) essential fatty acids, stem cells, aswell as neurotrophic elements such as for example brain-derived neurotrophic element (BDNF), ciliary neurotrophic element (CNTF), glial cell-line produced neurotrophic element (GDNF) and nerve development element (NGF) [25-34]. To the list other organic compounds could be added, specifically phytocannabinoids (pCBs) and endogenous cannabinoids (eCBs), predicated on 3rd party studies that recorded their neuroprotective results in ocular cells [35-44]. With this review, we summarize the primary results of preclinical research that support the great things about pCBs and eCBs as fresh neuroprotective agents, possibly beneficial to prevent, decelerate or even treatment glaucoma and retinal neurodegenerative illnesses. 2.?PHYTOCANNABINOIDS AND ENDOCANNABINOIDS: SYNTHESIS AND Creation The pCBs family members is most beneficial represented from the active component of cannabis (or Flom 1975Purnell and Gregg, 1975Cooler and Gregg 1977Flach 2002Tomida 2006Cin, RatEyeIOP reductionGlaucomaColasanti 1990MouseAnterior EyeIOP reductionGlaucomaCaldwell 2013DogEyeIOP reductionGlaucomaFischer 2013RabbitCorneaIOP reductionGlaucomaHingorani 2012RatRetinal Ganglion CellsCell protectionGlaucomaEl-Remessy 2003 Crandall 2007RatRetinal Neuronal CellsCell protectionDiabetic retinopathyEl-Remessy 2006ChickRetinal SectionCell protectionDiabetic retinopathy and glaucomaAraujoa 2017 Open up in another windowpane 5.?ENDOCANNABINOIDS AND RETINAL Safety eCBs display neuroprotective effects in various types of retinal neurodegeneration [35, 37-39,110]. Retinal ischemia versions, induced by chemical substances or severe elevation of IOP, influence the viability of a number of amacrine, pole bipolar and RGC cells and result in increased glutamate amounts and activation of ionotropic glutamate (NMDA and AMPA) receptors. As a result, intracellular calcium mineral ions and NOS activity boost, leading to glutamate-mediated excitotoxic retinal cell loss of life [116, 117]. For the reason that framework, AEA generates a neuroprotective impact against retinal cell loss of life induced by high IOP, through engagement of CB1 and TRPV1 [35]. Specifically, obstructing AEA degradation with the precise FAAH inhibitor URB587, or mimicking this impact utilizing the non-hydrolysable analogue of AEA, methanandamide, confers retinal neuroprotection against high IOP-induced cell loss of life [35]. Furthermore, CB1 was reported to lessen IOP the -adrenergic program, through inhibition of norepinephrine launch [118]. Inside a rat style of optic nerve axotomy, URB587 promotes retinal ganglion cell neuroprotection through CB1, and its own effectiveness declines with age group and is connected to a substantial upsurge in AEA amounts. In parallel, a reduction in the AEA congener a system involving CB1 as well as the PI3K/Akt and/or MEK/ERK1/2 signaling pathways [110]. In any other case it’s been demonstrated that deletion of CB1 or treatment of diabetic mice with CB1 antagonist SR141716 avoided retinal cell loss of life inside a mouse style of DR, aswell as in human being major retinal endothelial cells (HREC) subjected to high blood sugar, by reducing MAPK activation, oxidative tension and inflammatory signaling [119]. Also dental PEA provided for 90 days seems to decrease IOP in ocular hypertensive individuals [120], probably by raising AEA content, that’s low in glaucomatous eye [99], through inhibition of its degradation [121]. 2-AG was discovered to lessen IOP inside a focus- and CB1-reliant way [122, 123], and even inside a murine style of disease MAGL blockade can lower IOP by increasing endogenous eCB amounts [123] and therefore offering indirect neuroprotection. Oddly enough, several research reported that TRPV1 takes on a major part like a mediator of RGC function and success [124-126]. In-line.