Protective Neuropeptides VIP and PACAP Surge in the Lupus Brain — but Can't Fully Prevent Vascular Damage | Research

The takeaway

In lupus mice, brain blood vessel damage worsened with age while protective neuropeptides VIP and PACAP were upregulated — especially in the striatum — but this natural defense response wasn't enough to prevent endothelial dysfunction.

VIP/PACAP system strongly induced in striatum
The brain's endogenous neuropeptide defense system was robustly activated in response to lupus-related vascular damage, but could not prevent progressive endothelial dysfunction

What the researchers found

In NZBWF1 lupus mice compared to controls:

**Hippocampus**: Mild endothelial dysfunction markers (altered tPA, uPA, ICAM-1, VCAM-1, eNOS, KLF4) that worsened with age (2 vs. 7 months). VIP/PACAP system showed moderate changes.

**Striatum**: Robust endothelial activation markers even in young mice, with significant upregulation of the VIP/PACAP system including VIP, PACAP, and their receptors (PAC1, VPAC1, VPAC2). This suggests the striatum is more vulnerable to lupus-related vascular damage.

The key insight: the brain's endogenous neuropeptide defense system (VIP/PACAP) is activated in response to vascular damage but cannot effectively counteract the ongoing autoimmune injury.

Why it matters

Neuropsychiatric lupus (NPSLE) affects up to 75% of lupus patients but remains poorly understood and hard to treat. This study reveals that brain blood vessel damage is a key pathogenic mechanism and identifies the VIP/PACAP system as an endogenous protective response. This opens the door to therapeutic strategies using exogenous VIP or PACAP peptides — or their analogs — to boost the brain's natural defense against lupus-related vascular injury.

How the study worked

Researchers used NZBWF1 mice (a spontaneous lupus model) at 2 months (pre-disease) and 7 months (active disease) of age. Gene and protein expression of endothelial markers (tPA, uPA, ICAM-1, VCAM-1, BDNF, eNOS, KLF4) and neuropeptide system components (VIP, PACAP, PAC1, VPAC1, VPAC2) were measured in dissected hippocampus and striatum using qPCR and protein analysis techniques.

What this study cannot tell us

The study was conducted in mice, and the NZBWF1 model may not fully replicate all features of human NPSLE. Only two time points were assessed. Functional outcomes (behavior, cognition, blood-brain barrier permeability) were not directly measured. The study identified correlations between endothelial dysfunction and neuropeptide changes but did not establish causation or test whether exogenous VIP/PACAP could prevent the damage.

How to read the evidence

This is a preclinical study using a spontaneous lupus mouse model with molecular endpoint analysis. It provides important mechanistic insights but lacks functional outcome data and human validation.

When this study was published

Published in 2023, this study is recent and addresses an underexplored area — the role of neuropeptides in neuropsychiatric lupus pathology.

The bigger picture

VIP and PACAP are increasingly recognized as endogenous neuroprotective and anti-inflammatory peptides with therapeutic potential in autoimmune diseases. This study adds lupus neuropsychiatric disease to the growing list of conditions where these peptides mount a natural — but ultimately insufficient — defense response, supporting the rationale for exogenous peptide supplementation as a therapeutic strategy.

Questions still open

Would exogenous VIP or PACAP administration protect brain vasculature and improve neuropsychiatric outcomes in lupus models?
Why is the striatum more vulnerable to lupus-related endothelial dysfunction than the hippocampus?
Could VIP/PACAP receptor agonists be developed as targeted therapies for neuropsychiatric lupus?

Common questions

What are VIP and PACAP, and why are they important in lupus?

VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) are naturally produced brain peptides that protect blood vessels and reduce inflammation. In lupus mice, the brain increased production of these peptides in response to autoimmune blood vessel damage — essentially trying to heal itself — but the protection wasn't sufficient to stop the damage.

Could these neuropeptides be used as a treatment for lupus brain disease?

Potentially — this study shows the brain's own VIP/PACAP system tries but fails to prevent lupus vascular damage. Giving additional VIP or PACAP as a medication could theoretically boost this natural defense beyond what the body can produce alone. However, this has not yet been tested in lupus models.

Read the original research

Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus.

International journal of molecular sciences, 24(13)

View on PubMed ↗Publisher’s paper ↗

Citation

Lee, Jayden; Thomas Broome, Sarah; Jansen, Margo Iris; Mandwie, Mawj; Logan, Grant J; Marzagalli, Rubina; Musumeci, Giuseppe; Castorina, Alessandro. (2023). Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus.. International journal of molecular sciences, 24(13). https://doi.org/10.3390/ijms241311118