Additional Table 2.

Preclinical studies of N-acetylcysteine or N-acetylcysteineamine

Study	Rigor	Species, Sex, Weightor Age	Model, Controls	Dose, Time to first dose	Time of Outcome Assay, Outcome
Xiong, 1999	Randomization, NS; Blinded, NS	Rat, Male, 200-350g	Moderate CCI; Sham-CCI, CCI-saline	163mg/kg 30 min	1 h–14 d Brain GSH ↑ 3 h Mitochondrial GSH ↑ 14 d Mitochondrial GSH ↑ 12 h Mitochondrial State ↑ 3dMitochondrial Ca+2uptake ↑ 14dMitochondrial Ca+2uptake ↑
Thomale, 2006	Randomization, Yes; Blinded, NS	Rat, Male, 300–350g	Moderate CCI, Sham-CCI	163mg/kg 15 min, 2h, 4h	1 d Intercranial Pressure ↑ 1 d Edema → 1 d LV →
Yi, 2005	Randomization, NS; Blinded, NS	Rat,Male,350–400g	Moderate FPI, Sham-CCI, CCI-saline	163 mg/kg 5min	6 h–1 d Heme Oxidase 1 ↑ 1 d LV ↑
Yi, 2006	Randomization, NS; Blinded, NS	Rat, Male,350–400g	Moderate FPI, Sham-FPI, FPI-saline	163 mg/kg 5min	6h, 24hCortical complexin 1 ↑ 6 h Cortical complexin 2 ↑ 1 d, Cortical neurons ↑ 1 d Hippocampal neurons ↑
Hicdonmez, 2006	Randomization, Yes; Blinded, NS	Rat, Male,280–320g	Moderate WD, Not specified control group	150 mg/kg15min	2–12hMalondialdehyde ↑ 12 h SOD ↑ 2–12 h Glutathione Peroxidase ↑ 2–12 h Catalase → 2–12 h Frontal neurons ↑ 2–12 h Caspase 3 positive cells ↑
Chen, 2007	Randomization, NS; Blinded, NS	Rat, Male,250–300g	Moderate WD, Sham-WD	150 mg/kg 15min, 1, 2, and 3d	3 d NF-kB ↑ 3 d IL-1b, TNFa, IL-6 ↑ 3 d ICAM-1 ↑ 3 d Edema ↑ 3 d Blood brain barrier permeability ↑
Abdel Baki, 2009	Randomization, NS; Blinded, NS	Rat, Male,250–300g	Moderate CCI, Sham-CCI	150mg/kg 1h, 1d, 2d	7 d APA Entrances → 7 d APA Time to first entrance → 14 d Myelin →
Haber,2013	Randomization, NS; Blinding, NS	Rat,250–300g	Moderate CCI, sham-CHI-saline, CCI-saline,	150mg/kg 1h, 1d, 2d	7 d, Conflict APA → 7 d Spaced APA → 2 d MG →
Senol, 2014	Randomization, Yes; Blinded, NS	Rat, Male, 4 months	ModerateWD, Sham-WD	150 mg/kg 15min, 1h, 1, 2, and 3h	3 d Malondialdehyde ↑ 3 d Glutathione ↑ 3 d Retinol ↑ 3 d b -carotene ↑ 3 d Ascorbate ↑ 3 da-Tocopherol ↑ 3 d IL-1b, IL-4 ↑
Pandya, 2014	Randomization, Yes; Blinded, Yes	Male, Rat, 300–350g	Moderate CCI, CCI-Vehicle	150mg/kg 30 min, followed by 18.5mg/kg/h for 7d 150mg/kg NACA 30 min, followed by NACA 18.5mg/kg/h for 7d	1 d LV → 10 d MWM → 1 d LV ↑ 7 d Lipid peroxidation ↑ 7 d Protein nitrosylation → 10 d MWM ↑
Eakin, 2014	Randomization, Yes; Blinded, Yes	Male, Rat, 350–400g	Moderate FPI, Sham-FPI	50 mg/kg 30 min, 1, 2 and 3 d	10–13 d MWM ↑ 14 d MWM probe trial ↑
Kawoos, 2017	Randomization, Yes; Blinded, NS	Rat, Male,300–350g	Multiple Blast Intensities, Blast-saline	500 mg/kg NACA 2 h	2.5 hBlood brain barrier permeability ↑ 1–4 d Intercranial Pressure ↑
Chen, 2017	Randomization, Yes; Blinded, Yes	Male, Rat, 4 months	Moderate CCI, Sham-CCI	100mg/kg 5 min	1 d GSH ↑ 1 d Malondialdehyde ↑ 1 d NO ↑ 1 d NSS ↑ 1 d LV ↑ 1 d Edema ↑ 1 d Connexin 40 expression ↑
Haber,2018	Randomization, Yes; Blinding, No	Rat,Male,250–300g	Moderate CCI, Sham-CCI, CCI-saline	150mg/kg 1h, 1d, 2d	14 d Myelin → 14 d Oligodendrocytes → 14 d Oligodendrocyte apoptosis → 2–7 d MG →
Sangobowale,2018a	Randomization, Yes; Blinded,Yes	Rat, Male,250–300g	Moderate CCI, Sham-CCI, CCI-saline	75 mg/kg 6hfollowed by 1d, 2d	7 d BM ↑ 7 d APA Entrances ↑ 7 d APA Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin →
				75 mg/kg 12hfollowed by 1d, 2d	7 d BM ↑ 7 d APA Entrances → 7 d APA Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin →
				75 mg/kg 1d, 2d, 3d	7 d BM ↑ 7 d APA, entrances ↑ 7 d Time to first entrance ↑ 14 d Hippocampal MAP2 ↑ 14 d Myelin ↑
		Mouse, Male,28–30g	Moderate CHI, Sham-CHI, CHI-saline	75 mg/kg 12h, 1d, 2d	7 d BM → 7 d APA Entrances ↑ 7 d APA Time to first entrance ↑ 14 d Hippocampal MAP2 → 14 d Myelin →
				75 mg/kg 1d, 2d, 3d	7 d APA, entrances → 7 d APA, Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin →
Sangobowale,2018b	Randomization, Yes; Blinded, Yes	Mouse, Male,28-30g	Moderate CHI, Sham-CHI, CHI-saline	75 mg/kg 12h, 1d, 2d	2–14dOligodendrocytes → 14 d oligodendrocyte apoptosis →
Zhou	Randomization, Yes; Blinded, Yes	Mouse, Male, 28–32g	Moderate WD, Sham-WD, WD-saline	100mg/kg NACA 1h	1–3dNSS ↑ 1 d Heme Oxidase 1 ↑ 1 d NAD(P)H quinine oxidoreductase-1 ↑ 1 d Apoptosis ↑ 1 d Nuclear respiratory factor 1 ↑ 1 d Malondialdehyde ↑ 1 d Superoxide dismutanse ↑ 1 d lutathione peroxidase ↑ 1 d Fluro Jade positive cells ↑

Rigor for each study is provided following by injury model, species plus severity, control groups, and the MINO dosing. Time after injury is followed by whether NAC or NACA improved (↑) or had no difference (→) in the experimental outcome. APA: Active place avoidance; BM: Barnes maze; CCI: controlled cortical impact; CHIL: closed head injury; FPI: fluid percussion injury; GSH: glutathione; LV: lesion volume; MAP2: microtubule associated protein 2; MWM: Morris water maze; NORT: novel object recognition; NS: not specified; NSS: neurological severity score; WD: weight drop.