Astrocytic TRPV1-induced endogenous neurotrophic factors protect dopaminergic neuron in Parkinson’s disease

다국어 초록 (Multilingual Abstract)

Recently capsaicin (CAP) neuroprotection of dopamine (DA) neurons by astrocytic transient receptor potential vanilloid 1 (TRPV1) derived ciliary neurotrophic factor (CNTF) in MPP+ rat model of Parkinson’s disease (PD). Apart from CNTF, other neurotrophic factors associated with DA neuron were produced via astrocytic TRPV1 in MPP+-lesioned or α-syn-lesioned rat. Here I determined that among these neurotrophic factors, cerebral dopamine neurotrophic factor (CDNF) expressed by activation of TRPV1 prevented degeneration of DA neurons in MPP+-lesioned or α-syn-lesioned rat and improved amphetamine-induced rotational behavior. Astrocytic CDNF knockdown by shCDNF attenuated capsaicin-induced neuroprotection and behavioral recovery, indicating that astrocytic TRPV1-derived endogenous CDNF has neuroprotective properties in MPP+-lesioned rat. Collectively, these results indicate that astrocytic TRPV1 as the endogenous neuroprotective machinery in vivo might produce various neurotrophic factors required for DA neuron survival and have a promising therapeutic target for the treatment of PD.

목차 (Table of Contents)

• I. Introduction 12
• 1. Parkinson’s disease 12
• 2. History of Parkinson’s disease 12
• 3. Epidemiology of Parkinson’s disease 13
• 4. Pathogenesis of Parkinson’s disease 14
• 5. Therapy for Parkinson’s disease 15
• 5.1. Medications for Parkinson’s disease 16
• 5.1.1. Carbidopa-levodopa 16
• 5.1.2. Dopamine agonists 16
• 5.1.3. MAO-B/COMT inhibitors 17
• 5.2. Surgical treatment 17
• 5.2.1. Deep brain stimulation 17
• 6. Animal models of Parkinson’s disease 18
• 6.1. Sporadic animal model of Parkinson’s disease 18
• 6.1.1. MPTP/MPP+ 18
• 6.1.2. 6-OHDA 20
• 6.2. Genetic Parkinson’s disease animal model 20
• 6.2.1. α-synuclein 20
• 7. Dopamine neuron 22
• 8. Glia 22
• 8.1 Microglia in Parkinson’s disease 23
• 8.2 Astrocyte in Parkinson’s disease 24
• 9. TRPV1 26
• 9.1. TRPV1 in Parkinson’s disease 27
• 10. Neurotrophic factors in Parkinson’s disease 30
• 10.1. Neurotrophins family in Parkinson’s disease 30
• 10.1.1. Nerve growth factor 31
• 10.1.2. Brain-derived neurotrophic factor 31
• 10.2. Glial cell line-derived neurotrophic factor ligand Family 32
• 10.2.1. Glial cell line-derived neurotrophic factor 33
• 10.3. CDNF/MANF family 34
• 10.3.1. Mesencephalic astrocyte-derived neurotrophic factor 34
• 10.3.2. Cerebral dopamine neurotrophic factor 34
• II. Material and methods 38
• 1. Animals 38
• 2. Stereotaxic injection 38
• 3. Capsaicin injection 38
• 4. Adeno Association Viruses production 39
• 5. Stereotaxic AAV injections 39
• 6. Lenti virus injection 39
• 7. Immunofluorescence staining of Human PD brain 40
• 8. Immunohistochemistry staining of rats 42
• 9. Western blot 42
• 10. Stereology for cell counting 42
• 11. Behavioral test 43
• 12. Statistical analysis 43
• III. Abstract 44
• IV. Results 45
• 1. Expression of TRPV1, CDNF, and other neurotrophic factors in astrocyte of MPP+-lesioned rat models in vivo 45
• 2. TRPV1 produces endogenously NTF including CDNF in astrocyte of PD models. 56
• 3. CAP, attenuating microglia activation, increase production of CDNF in astrocyte of PD model in vivo 61
• 4. Capsaicin enhances endogenous production of CDNF via astrocytic TRPV1 in MPP+-lesioned SN in vivo 70
• 5. CDNF endogenously produced by CAP-activated astrocytes via TRPV1 prevents degeneration of dopamine neurons of MPP+-lesioned SN in vivo 77
• 6. CDNF deficiency in astrocytes attenuates CAP-induced neuroprotection and behavioral recovery in MPP+-lesioned rat SN in vivo 86
• 7. Endogenous expression of TRPV1, CDNF, MANF, and BDNF in astrocyte of A53T-α-synuclein model of Parkinson’s disease in vivo 93
• 8. Astrocytic CDNF produced by CAP protects degeneration of dopamine neurons in an A53T-α-synuclein model of Parkinson’s disease in vivo 100
• 9. Neurotrophic factors is expressed in astrocytes in the substantia nigra of human Parkinson’s disease 111
• IV. Summary 114
• V. Discussion 115
• VI. Bibliography 118