·       A ginseng-derived compound called notoginsenoside R1 significantly restored blood flow and promoted blood vessel formation in the brain post-stroke in mice.
·       Notoginsenoside R1 triggers a signaling cascade that increases levels of the bioenergetic molecule NAD+.
·       This signaling cascade improves energy metabolism in the brain regions near blood vessel damage.

Ischemic stroke — damage to the brain from interruption of its blood supply — remains a major cause of severe disability and mortality due to the limited capacity of the brain to regenerate. Current therapeutic methods focus on acutely blocked segments of the brain’s blood vessel network to restore cerebral blood flow. Accumulating evidence suggests that the development of new blood vessels (angiogenesis) in the affected brain regions is positively related to the survival and recovery of patients and experimental animals with stroke.

Zhu and colleagues published an article in Circulation Research showing that a molecule found in ginseng called notoginsenoside R1 promotes blood vessel generation in ischemic stroke. The research group from the Chinese Academy of Medical Sciences and Peking Union Medical College demonstrated that notoginsenoside R1 works by activating an enzyme called NAMPT necessary for synthesizing nicotinamide mononucleotide (NMN), a precursor to the vital multi-purpose molecule nicotinamide adenine dinucleotide (NAD+). These findings offer insight for exploring new therapeutic strategies for restoring brain health via R1 treatment after ischemic stroke.

Ginseng gets the blood going

Panax notoginseng is a famous traditional Chinese medicinal herb that has been used for thousands of years in China to promote blood circulation and relieve swelling and pain. The main active ingredients of ginseng improve microcirculation disturbance in mice with transient middle cerebral artery occlusion, a model of stroke.

Notoginsenoside R1 is a unique molecule in ginseng that, when taken before stroke, has protective effects. However, the role of notoginsenoside R1 in brain restoration on blood vessel formation after ischemic stroke has not been investigated. Emerging evidence suggests that R1 can stimulate proliferation and enhance tube formation ability in cultured human blood vessel cells and fish blood vessels.

The Nampt-NAD+ axis is linked to blood vessel formation

Although the process of brain recovery after stroke is not fully understood, the generation of blood vessels and brain cells are the main components of the complex process of brain healing. The NAMPT-NAD+ axis enhances the activity of blood vessel precursor cells, called endothelial progenitor cells, which includes proliferation, migration, and vessel formation. Also, the synthesis of NAD+ through NAMPT and the activity of enzymes called sirtuins, which depend on NAD+ to function, promote cell proliferation and improve energy metabolism. Therefore, NAMPT is likely to contribute to the formation of neovascularization after stroke.

Notoginsenoside R1 promotes blood vessel formation after ischemia

Zhu and colleagues used a rat model of middle cerebral artery occlusion to evaluate the promotion of R1 on angiogenesis after ischemic stroke in the brain. The results showed that the blood vessel density, total length, and amount of branching increased significantly after 7, 14, and 28 days of therapeutic administration of R1 by injection following stroke. Also, the number of new blood vessel cells that formed after stroke doubled, and the structure of brain microvascular endothelial cells was significantly improved after R1 treatment.

(Zhu et al., 2021 | Biomed Pharmacother.) Notoginsenoside R1 promotes angiogenesis after cerebral ischemia. These reconstructed images of blood vessels in the brain show that rats subjected to a model of stroke called middle cerebral artery occlusion/reperfusion (MCAO/R) have worse blood vessel structure compared to uninjured mice (Sham). Fourteen days of continuous administration of R1 treatment(MCAO/R+R1) resulted in significantly higher total vascular length, vascular density, and branching index than in the model group. These results were comparable to those seen with Nimodipine (MCAO/R+NIM), an anti-hypertensive drug that is used in treating cerebral hemorrhage.

This was accompanied by significantly increased cerebral blood flow and improved energy metabolism of the brain. These experimental results provide a theoretical basis for notoginsenoside R1 to support the formation of new functional blood vessels after cerebral ischemia.

(Zhu et al., 2021 | Biomed Pharmacother.) Notoginsenoside R1 improves energy metabolism after ischemia. Zhu and colleagues induced ischemic stroke in the right half of the brain. They then compared the amount of ATP metabolism measured by fluorescence intensity in the injured brain area (red) to an area of the uninjured brain (black). Mice that experienced a stroke (MCAO/R) but went untreated had a decrease in activity in the right side compared to the left side. Those that were treated with either notoginsenoside R1 (R1) or a known angiogenic factor called Dl-3-n-butylphthalide (NBP) had improved ATP metabolism in the injured brain half. These results are quantified in the right plot.

R1 activates the NAMPT-NAD+-SIRT cascade after ischemia

To determine how notoginsenoside R1 was working as an angiogenic factor, Zhu and colleagues found that notoginsenoside R1 treatment significantly reversed the decrease in the protein levels of NAMPT and downstream sirtuins induced by stroke, suggesting that R1 may promote angiogenesis by regulating the NAMPT-NAD+-sirtuin cascade.

(Zhu et al., 2021 | Biomed Pharmacother.) Notoginsenoside R1 upregulates NAMPT and sirtuin levels in cortex regions and increases the NAD+ concentration in serum after ischemic stroke. Quantification of the relative protein level of NAMPT (B) and SIRT1/2/3 (E) 7 days after stroke (MCAO/R) in mice that were treated with notoginsenoside R1 (R1). The serum level of NAD+ was quantified 7 and 28 days after ischemic stroke.

To verify the above experimental results, the Chinese research team used the NAMPT inhibitor FK866 to treat human blood vessels cells that were oxygen and glucose deprived — a mode for stroke in a dish. They found that FK866 treatment blocked the increase in NAMPT protein levels. These results suggest that the mechanism by which R1 promotes angiogenesis is related to the upregulation of NAMPT protein levels.

Based on the animal and cell culture results, Zhu and colleagues concluded that the promotion of notoginsenoside R1 on angiogenesis after cerebral ischemia may be mainly related to the regulation of the NAMPT-NAD+-SIRT1 cascade. These findings offer insight for exploring new therapeutic strategies for the restoration of brain health via R1 treatment after ischemic stroke and provide a new angle for treating stroke in people.