6-OHDA (=Oxidopamine)
- Pesticides
- Fumigants
- Phosphine
- Ethylene dibromide / dibromochloropropane
- Fungicides
- Hexachlorobenze
- Pentachlorophenol
- Phthalamides
- Captan, Folpet
- Dithiocarbamates
- Maneb*, Ziram
- Herbicides
- Bipyridyls
- Paraquat*, Diquat
- Phosphomethyl amino acids
- Glyphosate
- Chloroacetanilides
- Alachlor
- Chlorophenoxy Compounds
- 2,4-dichlorophenoxyacetate
- Bipyridyls
- Rodenticides
- Zinc Phosphide
- Fluoroacetate Derivatives
- α-naphthyl thiourea
- Anticoagulants
- Diphacinone, Bromdadialone
- Insecticides
- Anticholinesterases
- Organophosphates
- Parathion, Chlorpyrifos*
- Carbamates
- Aldicarb, Methomyl*
- Organophosphates
- Avermectins
- Ivermectin
- Botanicals
- Nicotine
- Rotenoids
- Rotenone*, Deguelin
- Organochlorines
- Cyclodienes
- Dieldrin*, Heptachlor
- Dichlorodiphenylethanes
- DDT*, methoxychlor
- Cyclohexanes
- Lindane, β-HCH
- Cyclodienes
- Pyrethroids
- Type I
- Permethrin*
- Type II
- Cypermethrin, Deltamethrin*
- Type I
- Other
- Nitromethylene
- Chloronicotinyl
- Phenylpyrazole
- Anticholinesterases
- Fumigants
lxvii) Mechanism
a. 6-OHDA enters neurons via the dopamine and noradrenaline reuptake transporters.
b.
lxviii) Animal model
a. No Lewy body formation
b. that 6-OHDA injection into the MFB causes the greatest degree of neuronal loss in the SN, whereas striatal injection will more likely generate partial lesions (Smith and Heuer, 2011) cf) this is also the ase in the book 2011 (book) animal model sof movement disorder, p267
lxix) Effect on Parkin
a. In PC12 cells & primary cortical neurons) MPP+ and 6OHDA → ↑ Parkin mRNA (Fig5a), ↓ Parkin protein (fig5B,E) (by enhancing proteosomal degradation) (Sun, 2013 #1321) J Neurosci. 2013; 33(6): 2398-407
b.
MPTP and 6-OHDA Down-regulate Parkin Activity And/or Its Expression — Boosting Cell Death Signaling
MPTP Model
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- MPTP penetrates BBB and is oxidized to MPP+ (active form).
- MPTP induces DA neuronal degeneration in substantia nigra in vivo.
- MPTP causes locomotor deficits in human and in vivo.
- MPP+ is worked as mitochondrial complex I inhibitor.
- MPTP induces s-nitrosylation of Parkin by NO in vivo. (Chung et al., 2004, PMID: 15105460) Science 2004; 304: 1328-1331
- S-nitrosylated Parkin dramatically reduces E3 ligase activity in vitro. (Chung, 2004 #1320) Science 2004; 304: 1328-1331
- MPP+ treatment reduces Parkin protein levels in vitro. (Sun et al., 2013, PMID: 23392669) J Neurosci. 2013; 33(6): 2398-407
6-OHDA Model
- 6-hydroxydopamine (6-OHDA)
- 6-OHDA enters neurons via the dopamine and noradrenaline reuptake transporters.
- 6-OHDA induces DA neuronal degeneration in substantia nigra in vivo.
- 6-OHDA causes locomotor deficits in human and in vivo.
- 6-OHDA generates reactive oxygen species (ROS).
- 6-OHDA treatment reduces Parkin protein levels in vitro. (Romaní-Aumedes et al., 2014, PMID: 25101677) Cell Death Dis. 2014; 5(8): e1364. (Sun et al., 2013, PMID: 23392669) J Neurosci. 2013; 33(6): 2398-407
Slide footer: Takeda Pharmaceutical Company Limited — 124 | Parkin GT project meeting | Mar 15, 2021 | Confidential - for internal use only
lxx) Effect of Parkin KO on 6-OHDA
a. Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity. BMC Neurosci. 2005;6:71
LPS
Mechanism
TLR4 is the LPS receptor.[28][29]
LPS can be sensed directly by hematopoietic stem cells (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection. This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, LPS causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L1.[24]
lxxi)
LPS in Mice
LPS in Rat
LPS Challenge Human
| In vitro | Ex vivo | In vivo | |
|---|---|---|---|
| Whole blood | |||
| Methods | In the test tube, this blood is mixed with LPS, → triggering an inflammatory response in WBCs. → The test compound can be added to the blood sample either before or after the LPS challenge, and the effect on the LPS-induced inflammatory response is measured over time. | the test compound is administered to the subject, → blood is drawn → and stimulated with the LPS challenge as described above. | healthy volunteers receive a safe dose of (iv, inhalation) LPS to induce a mild systemic inflammatory response that is monitored carefully → The effect of the test compound is then measured in the subject |
| Consequence: {Tawfik, 2020 #1935} |
innate immunity dominated the response to LPS in vivo, mainly markers related to monocytes and neutrophils in vivo and ex vivo, revealed that most of the markers were modulated in a similar pattern (68%),
| ||
| CNS? The amount of LPS entering brain parenchyma is about 0.025% of an intravenously administered dose |
{Peters van Ton, 2021 #1937} Five young males, IV of 2 ng/kg LPS) twice with a 7-day interval. → (plasma에서 ↑ various cytokines, but IL-1b Not measured)
| ||
| CHDR has protocols for all three. |
Transcranial sonography / Transcranial sonography in PD
| {Booth, 2015 #1745} REVIEW |
|
transcriptomics in PD
Uncertain Spans
- Pesticide flowchart 의 별표(*) 표시는 원본에 포함되어 있음. typography가 작은 점(
.)인지 별표(*)인지 모호하나 일관되게 별표로 옮김. - “lxvii)~lxxi)” 로마숫자 들여쓰기는 본문 작업자 수준의 reference 표기로, 사진의 들여쓰기 위치를 지키되 b 항목 빈 칸은 공란으로 옮김.
- Peters van Ton 2021 #1937 inset의 “Table 1” 숫자(예: 0.7733-…) 는 본문 글자가 매우 작아 본 markdown에는 옮기지 않고 evidence crop 만 보존함.
- Peters van Ton 2021 #1937 Fig 5 좌측/우측 패널의 cortical region (Frontal cortex / Parietal cortex / Occipital cortex / Temporal cortex) 와 subcortical region (Hippocampus / Amygdala / Thalamus) 라벨은 figure 안에 있어 evidence crop으로만 보존, 본문에는 옮기지 않음.