Table 1. Summary of benefits of permissive hypercapnia for CNS.

BBB: blood-brain barrier; CBF: cerebral blood flow; NSE: neuron-specific enolase; PD: Parkinson’s disease; TH: therapeutic hypercapnia; THMH: targeted therapeutic mild hypercapnia; TMH: targeted mild hypercapnia

Study	Year	Model	Effects on CNS	CO2
Yang et al. [12]	2019	Rat	TH ameliorated BBB damage and improved the neurologic outcome in a rat model of lateral fluid percussion injury.	80-100 mmHg
Vannucci et al. [13]	1997	Rat	During hypoxia-ischemia in the immature rat, CBF is better preserved during normocapnia and hypercapnia; the greater oxygen delivery promotes cerebral glucose utilization and oxidative metabolism for optimal maintenance of tissue high-energy phosphate reserves. Inhibition of glutamate secretion into the synaptic cleft and its attenuation of N-methyl-D-aspartate receptor activation would further protect the hypercapnic animal from hypoxic-ischemic brain damage.	55 mmHg
Wong et al. [15]	2020	Human	TMH during major surgery was associated with a stable increase in rSO2 from the baseline. Furthermore, postoperative delirium was lower in the TMN group.	45-55 mmHg
Tregub et al. [16]	2023	Rat	The exposure models where permissive hypercapnia and normobaric hypoxia were combined also had the most pronounced inhibitory effects on apoptotic signaling pathways, resulting in the maximum neuroprotective effect.	50 mmHg
Eastwood et al. [17]	2016	Human	THMH was feasible, appeared safe, and attenuated the release of NSE compared with targeted normocapnia.	50-55 mmHg
Tao et al. [18]	2013	Rat	TH preserves brain tissue and promotes functional neurological recovery through antiapoptotic mechanisms.	80-100 mmHg
Nadeev et al. [19]	2022	Mouse	High CO2 inhalation presumably initiates mitophagy via transient brain acidification and can treat PD-like symptoms in a rodent rotenone model of PD.	Three times a week, animals were placed in a closed glass cylinder, filled with 20% CO2 atmosphere for two minutes.