A naturally occurring compound, a neurosteroid called allopregnanolone, prevents the activation of the TLR4 protein in macrophages — a type of immune cell — and in the brain, new research in animal models found. This effect blocks an inflammatory response in cells, and may lead to new treatments for multiple sclerosis (MS), the scientists said.
The study, “Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain,” was published in the journal Nature Scientific Reports.
Neurosteroids are steroids produced in the brain that influence the behavior and the activity of nerve cells. One such compound, 3α,5α-THP or allopregnanolone, has shown beneficial effects in animal models of MS. Similar to its precursor called pregnenolone, it also showed effectiveness in clinical studies of traumatic brain injury, depression, schizophrenia, alcoholism, and other disorders.
Increased cellular signaling through TLR4 is seen during periods of physiological stress and in cases of traumatic brain injury. In macrophages, the TLR4 protein is part of a proinflammatory response that leads to the production of pro-inflammatory cytokines, a type of small signaling protein. TLR4 is also activated in neurons, but its precise mechanism and whether it is similar to that described in immune cells is not clear.
A research team from The University of North Carolina (UNC) School of Medicine and the University of Maryland evaluated whether allopregnanolone and pregnenolone can prevent proinflammatory signaling. For this purpose, they analyzed the effects of these steroids on TLR activation in macrophage-like mouse cells. TLR activation was induced by an inflammatory molecule known as lipopolysaccharide (LPS).
The researchers also looked at TLR4 signals and expression of corticotropin releasing factor (CRF) — known to activate TLR4 — in a brain region called ventral tegmental area (VTA) in rats with innate TLR4 activation. This strategy was used to avoid confounding effects of peripheral immune activation on brain inflammation. Of note, the team focused on the VTA because both TLR4 and neurosteroids alter drinking behavior through their actions in this area.
Results in mouse cells showed that both allopregnanolone and pregnenolone substantially blocked, or inhibited, the LPS-induced TLR4 activation in the cells, as was also shown by lower levels of proteins called TRAF6 and HMGB1, as well as the inflammatory mediators MCP-1 and TNFalpha.
The scientists found that these anti-inflammatory effects occurred via blocking the interaction of TLR4 with MD-2, a protein with which TLR4 forms a complex upon activation.
In the VTA experiments in rats, allopregnanolone, but not pregnenolone, reduced the levels of TRAF6, CRF, and MCP-1, as well as the binding of TLR4 to the α2 subunit of the GABAA receptor and the cellular protein MyD88, also implicated in TLR4 pro-inflammatory effects. This shows that, although the neurosteroid was administered into the abdomen, it had a significant effect in the brain.
“Pregnenolone’s effects in the brain were less pronounced, but inhibition of peripheral inflammation protects the brain as well because systemic inflammation affects organs throughout the body indirectly,” A. Leslie Morrow, PhD, the study’s senior author, said in a press release.
Overall, the scientists believe that blocking TLR4 has potential as a therapeutic approach.
“It has been very difficult to treat brain disease that involves inflammation, but allopregnanolone’s inhibition of TLR4 signaling activation in macrophages and the brain provides hope that we can develop better therapies to help millions of people suffering with these conditions,” Morrow said.
David Rubinow, MD, chair of the department of psychiatry at UNC-Chapel Hill, added that the findings have “great potential for spawning new, more effective primary and adjunctive treatments” for people with “brain disorders characterized by so-called neuroinflammation.”
Furthermore, the scientists wrote, “this work may inform the development of novel neuroactive steroids under development for treatment of various neurological and psychiatric disorders.”
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