NMN Delays Stroke in Mice Study

Summary

- Mouse with increased blood pressure and stroke predisposition have decreased NAD+ levels

- Defective cell recycling processes increased the risk of hypertension-related spontaneous stroke in mouse fed high-salt diets.

- NMN treatment reverses these processes to protect against stroke occurrence in these rodents.

Stroke is a leading cause of mortality and disability. Thus, we should know the symptoms of stroke to seizing golden rescue time. The information below are some symptoms of stroke.

1. Sudden confusion, trouble speaking, or difficulty understanding speech.

2. Sudden trouble walking, dizziness, loss of balance, or lack of coordination.

3. Sudden numbness or weakness in the face, arm, or leg, especially on one side of the body.

If the patients unfortunately get stroke, the stroke treatments that work best are available only within 3 hours of the first symptoms. Therefore, please stay calm if the patient has the above symptoms. And immediately send them to the hospital for medical treatment and note the time of the first symptom.

In fact, Stroke can be prevented. To prevent Stroke, we should know causes of stroke. Stroke has a range of risk factors including our genetic makeup and lifestyles that increase blood pressure, or hypertension. To date, there are no effective treatments for this disease, so understanding how high blood pressure or hypertension predisposes people to stroke may improve its preventive and therapeutic strategies. Although there have been hints for the role of the cell’s recycling processes known as autophagy in the development of hypertension-related stroke, this connection remains unclear.

An article, published in the journal Autophagy showing that defective autophagy favors hypertension-related spontaneous stroke by promoting dysfunction of the mitochondria, the cell structures responsible for generating energy. Researchers fed rats high-salt diets to cause hypertension and increase the risk of stroke and found a reduction of autophagy or cell recycling process in the rodent brains.

This impairment in autophagy was linked to mitochondrial dysfunction and depletion of the essential bioenergetic molecule nicotinamide adenine dinucleotide (NAD)+. When the researchers restored NAD+ levels with nicotinamide mononucleotide (NMN), they saw a reactivation of autophagy and reduced stroke development in the stroke-prone rats. These findings suggest that interventions aimed to boost NAD+ levels and activate autophagy may represent novel therapeutic strategies for subjects at higher risk to develop stroke.

Is Autophagy at the Heart of Stroke?

From single-cell organisms to the most complex multicellular ones, autophagy plays a vital role in the removal of damaged cellular components. One type of autophagy called mitophagy is devoted to the clearance of damaged mitochondria, ensuring mitochondrial quality control. Autophagy is usually activated in response to stress to remove dysfunctional mitochondria, which are then substituted with newly formed healthy ones.

Impairment of autophagy leads to the lack of a proper mitochondrial turnover with the resulting development of mitochondrial dysfunction, which can lead to the progression of cardiovascular diseases, including stroke. Mitochondrial dysfunction causes energy depletion, harmful oxygen-containing molecule buildup (oxidative stress), and inflammation, which are all major determinants of brain injury due to lack of blood flow. Along these lines, autophagy or cell recycling process inhibition would favor mitochondrial dysfunction and increase the susceptibility to stroke in the presence of risk factors.

NMN Reverses Autophagy Defects and Protects Against Stroke Occurrence

Researchers studied the link between autophagy impairment and spontaneous stroke development in stroke-prone hypertensive mice. The mice developed stroke, with an incidence of 100% after 7 weeks of high sodium and low potassium diet. In this model, the occurrence of stroke is preceded by the development of mitochondrial dysfunction, oxidative stress, and inflammation in brains and cerebral vasculature.

The scientists found that autophagy inhibition in these stroke-prone mice in response to high salt dietary feeding is dependent on the dramatic drop of intracellular NAD+ levels in the brain. But when they injected these rodents with the NAD+ precursor NMN (250 mg/kg) daily, they reversed NAD+ levels in the brain, resulting in improvements in autophagy, the clearance of damaged mitochondria, and mitochondrial function. They also saw an increase in the survival of blood vessel cells in the brains of mice predisposed to stroke with high salt diets.


(Forte et al. 2020 | Autophagy) NMN improved mitochondrial function and cell viability in cultured cells. Mouse blood vessel cells were treated with salt (NaCl) or an inhibitor of autophagy (siRNA) and then evaluated for the degree of mitochondrial damage (left) and viability (right). Both the salt and autophagy inhibitor treatments caused increases in mitochondrial damage and decreases in the percentage of live cells. These effects in both cases, however, were reversed by supplementation with NMN.

Importantly, NMN strongly blunted stroke occurrence in high salt-fed stroke-prone rats. Notably, more than half of the animals receiving NMN survived from stroke until the 12th week as compared to the untreated rats fed with a high salt diet. Notably, the protective effect of stimulating autophagy in preventing stroke occurred independent of blood pressure levels.


(Forte et al. 2020 | Autophagy) Stimulating autophagy with NMN increased stroke-free survival in rats fed high salt diets. The plots show the stroke occurrence in stroke-prone hypertensive rats (SHRSP) fed high salt diets (JD). These mice were then treated with either NMN (+NMN) or a stimulator of autophagy (+TAT BEC). In both cases, the prevalence of stroke was delayed nearly two-fold.

These results clearly indicate that autophagy impairment contribute to the development of cerebrovascular damage and stroke occurrence. Autophagy reactivation may favor the removal of dysfunctional mitochondria and limit the damage of endothelial and cerebral cells in response to high salt treatment, thereby delaying the onset of brain injury. In conclusion, these findings suggest that interventions aimed to activate autophagy and boost NAD+ levels may represent novel therapeutic strategies for subjects at higher risk to develop stroke.

Story Source

Forte M, Bianchi F, Cotugno M, Marchitti S, De Falco E, Raffa S, Stanzione R, Di Nonno F, Chimenti I, Palmerio S, Pagano F, Petrozza V, Micaloni A, Madonna M, Relucenti M, Torrisi MR, Frati G, Volpe M, Rubattu S, Sciarretta S. Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence. Autophagy. 2020 Aug;16(8):1468-1481. doi: 10.1080/15548627.2019.1687215. Epub 2019 Nov 12. PMID: 31679456; PMCID: PMC7469607.

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