P2P

• b. NHP
  • i. dopaminergic cell loss, α-syn aggregation, α-syn upregulation, and neuritic α-syn pathology
• lx) Effect on Parkin
  • a. MPTP induces s-nitrosylation of Parkin by NO in vivo. (Chung, 2004 #1320)
  • b. S-nitrosylated Parkin dramatically reduces E3 ligase activity in vitro. (Chung, 2004 #1320) Science 2004; 304: 1328-1331
  • c. 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
  • d.
• lxi) Effect of Parkin KO on MPTP
  • a. MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiol Dis. 2007;26(2):312-322
  • b. Parkin-knockout mice did not display increased vulnerability to intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res. 2013;24(2):280-287
• lxii) Subchronic MPTP mouse model
  • a. Charles K. Meshul, Ph.D. (Oregon Health & Science University)
  • a. (Churchill, 2017 #1540) MPTP (Santa Cruz Biotechnology, Dallas, TX, USA)-treated animals received intraperitoneal injections 5 days/week for 4 weeks. The dosages for MPTP (dissolved in normal saline and calculated as the base) that were used in our progressive model increased each week starting at 8 mg/kg for week 1, 16 mg/kg for week 2, 24 mg/kg for week 3, and 32 mg/kg for week 4. Their respective control group was injected with normal saline for the full duration of the MPTP injections. After the 4 weeks of MPTP or saline injections, a cohort of vehicle and MPTP-treated animals (4-wk VEH and 4-wk MPTP, respectively) were separated and euthanized 5 days after the last MPTP injection.
  • b. (Xu, 2019 #1539) received intraperitoneal injections of MPTP (Santa Cruz Biotechnology, Dallas, TX, USA) as described by Churchill et al (2017, 2019) for 5 days a week for 4 weeks. The dosages of MPTP (calculated as the base, dissolved in normal saline) used in our progressive model consisted of 10 mg/kg/day (week 1, 5d/wk), 20 mg/kg/day (week 2, 5d/wk), 24 mg/kg/day (week 3, 5d/wk) and 32 mg/kg/day (week 4, 5d/wk).
• lxiii) Rat model with MPTP
  • Cf) In contrast to mice, rats are relatively insensitive to MPTP [31]. Thus, rats injected with doses of MPTP comparable to those in mice do not exhibit any significant dopaminergic neurodegeneration for unknown reasons.
  • a.

Pesticides

• lxiv) resources: (Nandipati, 2016 #1045)(very good)

	MPTP	Rotenone	paraquat	Cyclodiene	DDT or its main metabolite DDE	lindane	dieldrin
	not a common environmental exposure	commonly used as an insecticide		↑(Hatcher, 2008 #1028) 2nd
Postmortem PD brains	(Davis, 1979 #1047) n=1, LB was found, along with SN destruction (Langston, 1999 #1046) n=3, addition, follow up of the drug addicts exposed to MPTP who developed Parkinsonism revealed the stable, and not progressive, course of their symptoms, along with no Lewy Body pathology in postmortem studies in any subjects.     lxv) Moderate to severe TH cell loss in SN     lxvi) active, ongoing inflammation with the presence of microglia, extracellular melanin, and neurodegeneration years after MPTP exposure, leading to the theory of "long-latency neurotoxicity" after agent exposure [18].				Although there are some reports of higher levels of DDT or its main metabolite DDE in the postmortem brain tissue of PD patients [52,53	higher levels of lindane in the postmortem PD brain tissue [55],	increased levels of dieldrin in the postmortem brain tissue of PD patients versus age-matched controls [53,55].
In vitro		(Van Laar, 2018 #1413) rotenone early increases mitochondrial and mtDNA replication and density specifically in distal axons (biogenesis), specifically at MAM in axons.
Mice model brain		Postmortem rat studies found that nearly half of substantia nigra and striatal neurons were lost. In addition, alpha-syn and polyubiquitin positive aggregates were observed in dopamine neurons in the SN, similar to the LBs found in PD [40,43]			], there has been no experimental evidence to support role of DDT or DDE in PD pathogenesis [54],	there is little experimental evidence to support a role in PD.
Epidemiological studies		Human epidemiological studies show that PD developed more often in people who reported use of rotenone compared with nonusers [53,54]. Among the most well known studies are those performed in the large AHS cohort [53]. In addition, the Farming and Movement Evaluation study (FAME), a small nested study within the AHS with only 69 cases and 237 controls, determined that rotenone was associated with PD regardless of the use of protective gloves [55].	studies, human epidemiological studies have found that not only is paraquat associated with PD occurrence, but the incidence of disease and the extent of paraquat exposure can sometimes strongly correlate [56]. However, the human evidence has been mixed. In addition to the negative pesticide studies described previously, a French case-control human study looking at specific pesticide exposures found that paraquat was not associated with PD, but this was possibly due to the study being performed in France, where paraquat is used at lower levels [72].

(Tanner, 2011 #1412) In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7).

Effect on Inflammation

6-OHDA (=Oxidopamine)

Pesticides

• Fumigants
  • Phosphine
  • [methyl bromide / ethylene dibromide / bromochloropropane]
• Fungicides
  • Hexachlorobenze
  • Pentachlorophenol
  • Phthalamides
    • Captan, Folpet
  • Dithiocarbamates
    • Maneb*, Ziram
• Herbicides
  • Bipyridyls
    • Paraquat*, Diquat
  • Phosphomethyl amino acids
    • Glyphosate
  • Chloroacetanilides
    • Alachlor
  • Chlorophenoxy Compounds
    • 2,4-dichlorophenoxyacetate
• Insecticides
• Rodenticides
  • Zinc Phosphide
  • Fluoroacetate Derivatives
  • α-naphthyl thiourea
  • Anticoagulants
    • Diphacinone, Bromdadialone

Uncertain Spans

• ‘Effect on Inflammation’ 셀과 ‘6-OHDA (=Oxidopamine)’ 셀은 본문 텍스트가 거의 없고 그림/도표만 들어 있어, 셀 위치와 내용 매핑은 시각 대조 결과를 따랐다.
• Pesticides 도식의 ‘Fumigants’ 항목은 좌측 컬럼이 사진 좌단에 거의 잘려 있어 ‘Phosphine’ 외 두 줄(“ethylene dibromide”, “bromochloropropane”)만 부분 판독되었다. 항목 안의 첫 줄은 사진에서 직접 판독 불가능.
• Pesticides 도식의 ‘Insecticides’ 분기는 사진 하단 밖으로 이어져 본 페이지에서는 분류명만 확인 가능.