Medical Hypotheses xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease Tian Tian a, Zhaoming Li b, Hong Lu a,⇑ a b
Department of Neurology and Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China
a r t i c l e
i n f o
Article history: Received 9 March 2015 Accepted 19 June 2015 Available online xxxx
a b s t r a c t Diabetic retinopathy (DR) is the leading cause of irreversible vision loss in adults. Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain. Evidences suggest that diabetic patients tend to show higher incidence of PD, advocating a shared mechanism between both the diseases. Interestingly, disruption of the dopaminergic system, which is an important causative factor in PD, has also been observed in DR. It is reported that retinal dopamine and tyrosine hydroxylase protein levels are downregulated, and dopaminergic amacrine cells appear to be degenerating in the animal models of DR. Further, injecting the diabetic mice with dopamine-restoring or dopamine-activating drugs already used to treat PD can restore dopamine levels and significantly improve diabetes-associated visual dysfunction in the early stage. Conversely, drugs already in use for insulin resistance also show protective effects in PD. Furthermore, a-Synuclein pathology of PD can be induced solely by high glucose in diabetic animal models. In conclusion, these findings establish an important role of dopamine deficiency as a common contributing factor in DR and PD. The changes in the ocular of diabetes involve dopamine metabolism disturbance, mimicking PD at the molecular level. Consequently, we could consider DR as at least partially the PD like molecular pathology in the eye. Importantly, indicating that dopamine decrease may play a role in DR will lead to a better understanding of the high rate of comorbidity reported between diabetes and PD, and reveal new therapeutic avenues for DR and other disorders that involve dopamine deficiency. Ó 2015 Published by Elsevier Ltd.
Introduction Diabetic retinopathy (DR) is a common and progressive complication of diabetes and the leading cause of irreversible vision loss in working-age adults [1]. The clinical hallmarks of DR include increased vascular permeability, microaneurysms and new blood vessels formation on the retina, leading to edema, ocular hemorrhage, lipid exudopaminete and eventual retinal vessel closure and nonperfusion [2,3]. Currently, combined control of glycemia, blood pressure, and serum lipid levels remains the most important strategy to prevent DR onset and progression. Once detected, ocular interventions including retinal laser photocoagulation, vitreoretinal surgery and intravitreal drug injection can help preserve vision [4]. The development of DR is a multifactorial process where genetic, metabolic and growth factors play important roles [5]. Although extensively studied, the pathogenesis of DR is still ⇑ Corresponding author. E-mail address: [email protected] (H. Lu).
insufficiently understood. Considerable evidence is emerging that indicates that the alteration of retinal neuronal function and viability is part of DR pathology [6–9]. Some reports have implicated the role of retinal neuron dopamine deficiency in the visual dysfunction of DR [10,11]. Parkinson’s disease (PD) has been defined as being characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain [12], we here hypothesize that, according to current researches, common pathophysiology affecting DR and PD. Could diabetic retinopathy be Parkinson’s disease in the eye? Diabetes is known to cause significant alterations in the retinal vasculature and breakdown of the blood–retinal barrier. However, DR is being widely recognized as a neurodegenerative disease as opposed to previously considered solely as a microvascular disease of the retina [13]. Extensive research has established the functional deficits in the neural retinas in diabetic patients [7–9] and the changes of neural retina prior to the onset of vascular compromise shortly after diabetes [8,9]. Furthermore, the apoptosis of neurons
http://dx.doi.org/10.1016/j.mehy.2015.06.016 0306-9877/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Tian T et al. Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.016
2
T. Tian et al. / Medical Hypotheses xxx (2015) xxx–xxx
and pathology of other cell types including glial activation, which is another feature of retinal neurodegeneration, were reported in diabetes [9,14–16]. Thus, it is concluded that neurodegeneration is an important component of DR. PD is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain and aggregation of a-Synuclein, named Lewy bodies in the remaining nigral neurons [12]. Emerging evidences suggest that diabetic patients tend to show higher incidence of PD, advocating a strong relationship and a shared mechanism between both the diseases [17–19]. Recent studies have established that ida-1 is an important modulator in Daf-2/Daf-16 insulin like signaling pathway and possibly a common link between PD and diabetes [18]. Despite the intensive research, the clinical and genetic relationships between diabetes and PD still remain unclear. Dopamine is a key neurotransmitter in both the brain and retina that supports motor, cognitive, and visual function. The delicate network of various retinal neurons ensures the accuracy of visual signal transmission, and dopamine plays an important modulatory role in this complicated process [20,21]. Interestingly, similar to the loss of dopaminergic neurons in substantia nigra of midbrain in PD, the morphological or functional degeneration of retinal dopaminergic amacrine cells has also been demonstrated during the early stage of Streptozotocin-induced diabetes, an animal model of type 1 diabetes. It is reported that dopamine levels decrease significantly in diabetic rat retina from the third week of hyperglycemia [10]. Loss of dopaminergic amacrine cells in the mouse retina was found after 6 months of diabetes, which may account for the development of visual deficits known to occur in diabetic subjects [11]. Still other studies suggest that retinal tyrosine hydroxylase protein levels are downregulated and dopaminergic amacrine cells appear to be degenerating in the diabetic rat retina [22]. More recently, Aung M.H. and colleagues demonstrate that retinal dopamine content is reduced in early stage of DR. Further, injecting the diabetic mice with dopamine-restoring (levodopa) or dopamine-activating drugs (dopamine receptor agonists) already used to treat PD can restore dopamine levels and significantly improve retinal function and thereby diabetes-associated visual dysfunction [23]. The study strongly suggests that diabetes-induced dopamine deficiency and dysfunction in the neural retina plays a pathogenic role in DR, and treatments targeting dopamine could be beneficial to patients with established diabetes. However, in my speculation it is unlikely for the vision to recover in the late stage of diabetes if the loss of dopaminergic amacrine cells in the retina has been detected, thus the retinal neuron damage would probably be irreversible. Together, these findings establish an important role of dopamine deficiency as a common contributing factor in DR and PD. Moreover, drugs already in use for insulin resistance also show protective effects in PD, thus possibly being a common link between diabetes and PD [19,24]. In addition, a-Synuclein is expressed in neural retinal cells [25] and a-Synuclein pathology of PD can be induced solely by expected high blood glucose in diabetic animal models [18]. Therefore, it is proposed that DR may be considered as the PD like molecular pathology in the eye. Taken together, a theoretical relationship between dopamine deficiency, DR, especially that associated with type 1 diabetes, and PD seems to exist. The changes in the ocular of diabetes involve dopamine metabolism disturbance, mimicking PD at the molecular level. Consequently, we could consider DR as at least partially the PD in the eye. Importantly, indicating that dopamine decrease, which is an important causative factor in PD, may play a role in DR will lead to a better understanding of the high rate of comorbidity reported between diabetes and PD, and reveal new therapeutic avenues for DR and other disorders that involve dopamine deficiency.
Conflict of interest None declared. Acknowledgments This study was supported by funds from the National Natural Science Foundation of China (81301087 and 81402380), China Postdoctoral Science Foundation (2013M540574 and 2014T70689) and Youth Innovation Funds Project of the First Affiliated Hospital, Zhengzhou University (to Tian Tian).
References [1] Sivaprasad S, Gupta B, Crosby-Nwaobi R, Evans J. Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. Surv Ophthalmol 2012;57:347–70. [2] Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48–58. [3] Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013;93:137–88. [4] Marozas LM, Fort PE. Diabetic retinopathy – update on prevention techniques, present therapies, and new leads. US Ophthalmic Rev 2014;7:54–8. [5] Giusti C, Gargiulo P. Advances in biochemical mechanisms of diabetic retinopathy. Eur Rev Med Pharmacol Sci 2007;11:155–63. [6] Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012;366:1227–39. [7] Jackson GR, Barber AJ. Visual dysfunction associated with diabetic retinopathy. Curr Diab Rep 2010;10:380–4. [8] Bearse MA, Han Y, Schneck ME, Adams AJ. Retinal function in normal and diabetic eyes mapped with the slow flash multifocal electroretinogram. Invest Ophthalmol Vis Sci 2004;45:296–304. [9] Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL. Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des 2007;13:2699–712. [10] Nishimura C, Kuriyama K. Alterations in the retinal dopaminergic neuronal system in rats with streptozotocin-induced diabetes. J Neurochem 1985;45: 448–55. [11] Gastinger MJ, Singh RS, Barber AJ. Loss of cholinergic and dopaminergic amacrine cells in streptozotocin-diabetic rat and Ins2Akita-diabetic mouse retinas. Invest Ophthalmol Vis Sci 2006;47:3143–50. [12] Boeve BF. Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol 2013;12:469–82. [13] Ola MS, Alhomida AS. Neurodegeneration in diabetic retina and its potential drug targets. Curr Neuropharmacol 2014;12:380–6. [14] Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 1998;47:815–20. [15] Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 1998;102:783–91. [16] Mohr S, Xi X, Tang J, Kern TS. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. Diabetes 2002;51:1172–9. [17] Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, et al. Diabetes and risk of Parkinson’s disease. Diabetes Care 2011;34:910–5. [18] Fatima S, Haque R, Jadiya P, Shamsuzzama, Kumar L, Nazir A. Ida-1, the Caenorhabditis elegans orthologue of mammalian diabetes autoantigen IA-2, potentially acts as a common modulator between Parkinson’s disease and diabetes: role of Daf-2/Daf-16 insulin like signalling pathway. PLoS One 2014;9:e113986. [19] Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson’s disease, insulin resistance and novel agents of neuroprotection. Brain 2013;136:374–84. [20] Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007;30:194–202. [21] Jackson CR, Ruan GX, Aseem F, Abey J, Gamble K, Stanwood G, et al. Retinal dopamine mediates multiple dimensions of light-adapted vision. J Neurosci 2012;32:9359–68. [22] Seki M, Tanaka T, Nawa H, Usui T, Fukuchi T, Ikeda K, et al. Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brainderived neurotrophic factor for dopaminergic amacrine cells. Diabetes 2004;53:2412–9. [23] Aung MH, Park HN, Han MK, Obertone TS, Abey J, Aseem F, et al. Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes. J Neurosci 2014;34:726–36. [24] Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest 2013;123:2730–6. [25] Martínez-Navarrete GC, Martín-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N. Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis 2007;13:949–61.
Please cite this article in press as: Tian T et al. Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.016
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease Tian Tian a, Zhaoming Li b, Hong Lu a,⇑ a b
Department of Neurology and Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China
a r t i c l e
i n f o
Article history: Received 9 March 2015 Accepted 19 June 2015 Available online xxxx
a b s t r a c t Diabetic retinopathy (DR) is the leading cause of irreversible vision loss in adults. Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain. Evidences suggest that diabetic patients tend to show higher incidence of PD, advocating a shared mechanism between both the diseases. Interestingly, disruption of the dopaminergic system, which is an important causative factor in PD, has also been observed in DR. It is reported that retinal dopamine and tyrosine hydroxylase protein levels are downregulated, and dopaminergic amacrine cells appear to be degenerating in the animal models of DR. Further, injecting the diabetic mice with dopamine-restoring or dopamine-activating drugs already used to treat PD can restore dopamine levels and significantly improve diabetes-associated visual dysfunction in the early stage. Conversely, drugs already in use for insulin resistance also show protective effects in PD. Furthermore, a-Synuclein pathology of PD can be induced solely by high glucose in diabetic animal models. In conclusion, these findings establish an important role of dopamine deficiency as a common contributing factor in DR and PD. The changes in the ocular of diabetes involve dopamine metabolism disturbance, mimicking PD at the molecular level. Consequently, we could consider DR as at least partially the PD like molecular pathology in the eye. Importantly, indicating that dopamine decrease may play a role in DR will lead to a better understanding of the high rate of comorbidity reported between diabetes and PD, and reveal new therapeutic avenues for DR and other disorders that involve dopamine deficiency. Ó 2015 Published by Elsevier Ltd.
Introduction Diabetic retinopathy (DR) is a common and progressive complication of diabetes and the leading cause of irreversible vision loss in working-age adults [1]. The clinical hallmarks of DR include increased vascular permeability, microaneurysms and new blood vessels formation on the retina, leading to edema, ocular hemorrhage, lipid exudopaminete and eventual retinal vessel closure and nonperfusion [2,3]. Currently, combined control of glycemia, blood pressure, and serum lipid levels remains the most important strategy to prevent DR onset and progression. Once detected, ocular interventions including retinal laser photocoagulation, vitreoretinal surgery and intravitreal drug injection can help preserve vision [4]. The development of DR is a multifactorial process where genetic, metabolic and growth factors play important roles [5]. Although extensively studied, the pathogenesis of DR is still ⇑ Corresponding author. E-mail address: [email protected] (H. Lu).
insufficiently understood. Considerable evidence is emerging that indicates that the alteration of retinal neuronal function and viability is part of DR pathology [6–9]. Some reports have implicated the role of retinal neuron dopamine deficiency in the visual dysfunction of DR [10,11]. Parkinson’s disease (PD) has been defined as being characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain [12], we here hypothesize that, according to current researches, common pathophysiology affecting DR and PD. Could diabetic retinopathy be Parkinson’s disease in the eye? Diabetes is known to cause significant alterations in the retinal vasculature and breakdown of the blood–retinal barrier. However, DR is being widely recognized as a neurodegenerative disease as opposed to previously considered solely as a microvascular disease of the retina [13]. Extensive research has established the functional deficits in the neural retinas in diabetic patients [7–9] and the changes of neural retina prior to the onset of vascular compromise shortly after diabetes [8,9]. Furthermore, the apoptosis of neurons
http://dx.doi.org/10.1016/j.mehy.2015.06.016 0306-9877/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Tian T et al. Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.016
2
T. Tian et al. / Medical Hypotheses xxx (2015) xxx–xxx
and pathology of other cell types including glial activation, which is another feature of retinal neurodegeneration, were reported in diabetes [9,14–16]. Thus, it is concluded that neurodegeneration is an important component of DR. PD is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain and aggregation of a-Synuclein, named Lewy bodies in the remaining nigral neurons [12]. Emerging evidences suggest that diabetic patients tend to show higher incidence of PD, advocating a strong relationship and a shared mechanism between both the diseases [17–19]. Recent studies have established that ida-1 is an important modulator in Daf-2/Daf-16 insulin like signaling pathway and possibly a common link between PD and diabetes [18]. Despite the intensive research, the clinical and genetic relationships between diabetes and PD still remain unclear. Dopamine is a key neurotransmitter in both the brain and retina that supports motor, cognitive, and visual function. The delicate network of various retinal neurons ensures the accuracy of visual signal transmission, and dopamine plays an important modulatory role in this complicated process [20,21]. Interestingly, similar to the loss of dopaminergic neurons in substantia nigra of midbrain in PD, the morphological or functional degeneration of retinal dopaminergic amacrine cells has also been demonstrated during the early stage of Streptozotocin-induced diabetes, an animal model of type 1 diabetes. It is reported that dopamine levels decrease significantly in diabetic rat retina from the third week of hyperglycemia [10]. Loss of dopaminergic amacrine cells in the mouse retina was found after 6 months of diabetes, which may account for the development of visual deficits known to occur in diabetic subjects [11]. Still other studies suggest that retinal tyrosine hydroxylase protein levels are downregulated and dopaminergic amacrine cells appear to be degenerating in the diabetic rat retina [22]. More recently, Aung M.H. and colleagues demonstrate that retinal dopamine content is reduced in early stage of DR. Further, injecting the diabetic mice with dopamine-restoring (levodopa) or dopamine-activating drugs (dopamine receptor agonists) already used to treat PD can restore dopamine levels and significantly improve retinal function and thereby diabetes-associated visual dysfunction [23]. The study strongly suggests that diabetes-induced dopamine deficiency and dysfunction in the neural retina plays a pathogenic role in DR, and treatments targeting dopamine could be beneficial to patients with established diabetes. However, in my speculation it is unlikely for the vision to recover in the late stage of diabetes if the loss of dopaminergic amacrine cells in the retina has been detected, thus the retinal neuron damage would probably be irreversible. Together, these findings establish an important role of dopamine deficiency as a common contributing factor in DR and PD. Moreover, drugs already in use for insulin resistance also show protective effects in PD, thus possibly being a common link between diabetes and PD [19,24]. In addition, a-Synuclein is expressed in neural retinal cells [25] and a-Synuclein pathology of PD can be induced solely by expected high blood glucose in diabetic animal models [18]. Therefore, it is proposed that DR may be considered as the PD like molecular pathology in the eye. Taken together, a theoretical relationship between dopamine deficiency, DR, especially that associated with type 1 diabetes, and PD seems to exist. The changes in the ocular of diabetes involve dopamine metabolism disturbance, mimicking PD at the molecular level. Consequently, we could consider DR as at least partially the PD in the eye. Importantly, indicating that dopamine decrease, which is an important causative factor in PD, may play a role in DR will lead to a better understanding of the high rate of comorbidity reported between diabetes and PD, and reveal new therapeutic avenues for DR and other disorders that involve dopamine deficiency.
Conflict of interest None declared. Acknowledgments This study was supported by funds from the National Natural Science Foundation of China (81301087 and 81402380), China Postdoctoral Science Foundation (2013M540574 and 2014T70689) and Youth Innovation Funds Project of the First Affiliated Hospital, Zhengzhou University (to Tian Tian).
References [1] Sivaprasad S, Gupta B, Crosby-Nwaobi R, Evans J. Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. Surv Ophthalmol 2012;57:347–70. [2] Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48–58. [3] Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013;93:137–88. [4] Marozas LM, Fort PE. Diabetic retinopathy – update on prevention techniques, present therapies, and new leads. US Ophthalmic Rev 2014;7:54–8. [5] Giusti C, Gargiulo P. Advances in biochemical mechanisms of diabetic retinopathy. Eur Rev Med Pharmacol Sci 2007;11:155–63. [6] Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012;366:1227–39. [7] Jackson GR, Barber AJ. Visual dysfunction associated with diabetic retinopathy. Curr Diab Rep 2010;10:380–4. [8] Bearse MA, Han Y, Schneck ME, Adams AJ. Retinal function in normal and diabetic eyes mapped with the slow flash multifocal electroretinogram. Invest Ophthalmol Vis Sci 2004;45:296–304. [9] Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL. Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des 2007;13:2699–712. [10] Nishimura C, Kuriyama K. Alterations in the retinal dopaminergic neuronal system in rats with streptozotocin-induced diabetes. J Neurochem 1985;45: 448–55. [11] Gastinger MJ, Singh RS, Barber AJ. Loss of cholinergic and dopaminergic amacrine cells in streptozotocin-diabetic rat and Ins2Akita-diabetic mouse retinas. Invest Ophthalmol Vis Sci 2006;47:3143–50. [12] Boeve BF. Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol 2013;12:469–82. [13] Ola MS, Alhomida AS. Neurodegeneration in diabetic retina and its potential drug targets. Curr Neuropharmacol 2014;12:380–6. [14] Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 1998;47:815–20. [15] Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 1998;102:783–91. [16] Mohr S, Xi X, Tang J, Kern TS. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. Diabetes 2002;51:1172–9. [17] Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, et al. Diabetes and risk of Parkinson’s disease. Diabetes Care 2011;34:910–5. [18] Fatima S, Haque R, Jadiya P, Shamsuzzama, Kumar L, Nazir A. Ida-1, the Caenorhabditis elegans orthologue of mammalian diabetes autoantigen IA-2, potentially acts as a common modulator between Parkinson’s disease and diabetes: role of Daf-2/Daf-16 insulin like signalling pathway. PLoS One 2014;9:e113986. [19] Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson’s disease, insulin resistance and novel agents of neuroprotection. Brain 2013;136:374–84. [20] Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007;30:194–202. [21] Jackson CR, Ruan GX, Aseem F, Abey J, Gamble K, Stanwood G, et al. Retinal dopamine mediates multiple dimensions of light-adapted vision. J Neurosci 2012;32:9359–68. [22] Seki M, Tanaka T, Nawa H, Usui T, Fukuchi T, Ikeda K, et al. Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brainderived neurotrophic factor for dopaminergic amacrine cells. Diabetes 2004;53:2412–9. [23] Aung MH, Park HN, Han MK, Obertone TS, Abey J, Aseem F, et al. Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes. J Neurosci 2014;34:726–36. [24] Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest 2013;123:2730–6. [25] Martínez-Navarrete GC, Martín-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N. Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis 2007;13:949–61.
Please cite this article in press as: Tian T et al. Common pathophysiology affecting diabetic retinopathy and Parkinson’s disease. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.016
