Insights of Chinese herbal medicine for mitochondrial dysfunction in chronic cerebral hypoperfusion induced cognitive impairment: Existed evidences and potential directions

Abstract

Chronic cerebral hypoperfusion (CCH) is one of the main pathophysiological markers of cognitive impairment in central nervous system diseases. Mitochondria are cores of energy generation and information process. Mitochondrial dysfunction is the key upstream factors of CCH induced neurovascular pathology. Increasing studies explored the molecular mechanisms of mitochondrial dysfunction and self-repair for effective targets to improve CCH-related cognitive impairment. The clinical efficacy of Chinese herbal medicine in the treatment of CCH induced cognitive impairment is definite. Existed evidences from pharmacological studies have further proved that, Chinese herbal medicine could improve mitochondrial dysfunction and neurovascular pathology after CCH by preventing calcium overload, reducing oxidative stress damage, enhancing antioxidant capacity, inhibiting mitochondria-related apoptosis pathway, promoting mitochondrial biogenesis and preventing excessive activation of mitophagy. Besides, CCH mediated mitochondrial dysfunction is one of the fundamental causes for neurodegeneration pathology aggravation. Chinese herbal medicine also has great potential therapeutic value in combating neurodegenerative diseases by targeting mitochondrial dysfunction.

Keywords: Chinese herbal medicine; chronic cerebral hypoperfusion; cognitive impairment; mitochondria; mitochondrial dysfunction.

FIGURE 1

The mechanism of mitochondrial dysfunction after CCH. CCH related excitotoxicity induced mPTP formation (A), which leads to calcium overload. Chronic hypoxia inhibits mitochondrial oxidative phosphorylation, resulting in excessive production of ROS, inhibition of ETC complex and antioxidant enzyme inactivation, eventually oxidative stress (B). Calcium overload and oxidative stress rupture mitochondrial outer membrane (C), trigger the release of pro-apoptotic factors (Cyt C and AIF) (D), which mediate Caspase cascade and DNA fragmentation, respectively, leading to apoptosis/cell death (E). Meanwhile, Bcl-2 family proteins play a key role in regulating the release of anti-apoptotic factors (D). Mitochondrial dysfunction is the key to CCH induced neurovascular injury: endothelial dysfunction, chronic neuroinflammation and myelination impairment.

FIGURE 2

The mechanism of mitochondrial autoregulation disorder after CCH. Consistent hypoperfusion seriously damages mitochondrial dynamics. Mitochondrial fission is aggravated and causes overactivation of mitophagy, which finally leads to swelling and rupture (A). Low level of PGC-1α after CCH promotes oxidative stress, microglia activation and neuron death (B).

FIGURE 3

Therapeutic mechanisms of Chinese herbal medicine targeting mitochondrial dysfunction and self-regulation disorder after CCH. (A) Stabilizing mitochondrial membrane potential, reducing mitochondrial calcium overload, and preventing mitochondrial rupture by alleviating excitotoxicity. (B) Enhancing antioxidant enzyme activity, protecting ETC to reducing ROS production. (C) Regulating the expression of Bcl-2 and Bax to reduce the release of mitochondrial pro-apoptotic factors. (D) Upregulating PGC-1α and inhibiting mitophagy overactivation to restore mitochondrial self-regulation.