A small molecule called K-7174 alleviated the neuropsychiatric symptoms of systemic lupus erythematosus (SLE) and also helped improve cognitive function in a recent study in mice.
The researchers found that treatment with this molecule may protect against neuropsychiatric SLE (NPSLE) by selectively maintaining the blood-brain barrier (BBB) in the body.
“This study identified K-7174 as a valuable small molecule drug for the treatment of NPSLE,” the researchers wrote.
Non-neurological symptoms of lupus, including enlarged spleen and kidney problems, were also reduced with K-7174 treatment.
the study, “Small molecule compound K-7174 reduces neuropsychiatric symptoms in lupus-prone micewas published in a magazine brain research.
Investigation of K-7174 in SLE
SLE, an autoimmune condition, is characterized by inflammation in multiple systems of the body. In some cases, lupus affects the nervous system and can cause neuropsychiatric symptoms such as cognitive impairment, headaches, and memory loss in patients.
However, the underlying causes of NPSLE remain poorly understood and this complication contributes significantly to patient disease burden.
It has been suggested that disruption of the BBB may be a driver of NPSLE as it allows inflammatory molecules that cause neuronal damage to reach the brain.
“Targeting the BBB could be an important strategy for the treatment of NPSLE,” the researchers wrote.
K-7174 is an investigational compound with immunomodulatory and anti-inflammatory properties. It belongs to a class of substances called proteasome inhibitors that are laying the foundation for cancer treatments, and this type of treatment may affect the cellular processes involved in maintaining her BBB. is also suggested.
Therefore, Chinese researchers wondered whether K-7174 is a promising treatment for NPSLE.
The team tested their hypothesis in a mouse model of lupus. Animals were injected with K-7174 (30 mg/kg) three times a week or left untreated for a total of 6 weeks.
As expected, untreated mice with lupus showed signs of autoimmune disease, such as enlarged spleens and the presence of lupus-associated antibodies in the bloodstream. They also showed signs of lupus nephritis, characterized by high levels of protein in the urine and damage to the kidneys.
These symptoms were alleviated in mice given K-7174, indicating that “K-7174 can ameliorate lupus-like symptoms.”
In particular, K-7174 was able to combat cognitive impairment, the most common symptom of NPSLE in human patients.
During behavioral testing, untreated lupus mice showed evidence of cognitive problems compared with healthy mice. Such deficits included spatial learning and memory problems, all of which were significantly alleviated with K-7174 treatment.
Analysis of mouse brain tissue revealed that lupus is associated with neuronal degeneration and damage to the BBB.
A series of experiments provided evidence that K-7174 can protect BBB integrity and prevent neuronal damage in SLE. Mice treated with K-7174 had less neuronal damage and higher levels of key BBB proteins than untreated mice.
Levels of albumin (a large protein that can enter the brain when the BBB is damaged and leaky) were elevated in lupus mouse brains, but this was reduced with K-7174 treatment.
In addition, K-7174 is known to proliferate and promote BBB degradation during inflammation, while increasing levels of proteins important for maintaining BBB integrity and preventing the passage of unwanted substances. demonstrated the ability to inhibit cells.
A series of other experiments in mice and cell culture found that lactate, a by-product of glucose (blood sugar) breakdown in lupus mice, was increased and associated with BBB breakdown. Lactic acid can be used as an energy source for nerve cells, but excessive amounts can lead to cell damage and death.
K-7174 was associated with lactate reduction and subsequent protection of the BBB. This appeared to be related in part to the ability of the molecule to activate a signaling pathway called MCT4/NKAP/CREB that promotes the production of the critical BBB. protein.
Overall, the results suggest that “K-7174 can protect the integrity of the BBB, thereby reducing neuronal cell death and cognitive impairment,” the researchers wrote. There is nothing to say that a specific molecular mechanism has not yet been elucidated.