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Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with
Birgit Kastberger1, Stefan Winter1, Hemma Brandstätter1
1Ever Pharma, Oberburgau 3, Unterach am Attersee, 4866, Austria.
Insights
Cerebrolysin improved health and longevity in a mouse model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), but did not impact CADASIL-specific pathology. This suggests potential benefits for aging disorders.
Area of Science:
- Neurology
- Genetics
- Pharmacology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic neurological disorder with no current therapy.
- CADASIL is caused by NOTCH3 gene mutations, leading to symptoms like stroke, dementia, and premature death.
Purpose of the Study:
- To investigate the therapeutic potential of Cerebrolysin, a neuropeptide drug, in a murine model of CADASIL.
- To evaluate the effects of Cerebrolysin on histopathological and functional outcomes in NOTCH3 mutant mice.
Main Methods:
- Twelve-month-old NOTCH3 mutant mice (n=176) received Cerebrolysin or vehicle treatment for nine weeks.
- Histopathological and functional outcomes were assessed over the following ten months.
- Molecular changes, including gene expression (CGRP, SIRT6, IGF-1) and neurovascular laminin, were analyzed.
Main Results:
- Cerebrolysin treatment enhanced spatial memory, improved overall health, reduced epigenetic aging, and prolonged lifespan in the CADASIL mice.
- However, Cerebrolysin did not affect CADASIL-specific white matter vacuolization.
- Molecularly, Cerebrolysin increased CGRP and SIRT6 expression, decreased IGF-1, and normalized neurovascular laminin.
Conclusions:
- Cerebrolysin promotes longevity and healthy aging in a CADASIL mouse model without altering the core disease pathology.
- Cerebrolysin may be a potential therapeutic option for CADASIL and other age-related disorders.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether the multi-modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve-month-old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL-specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene-Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)-like protein 6 (SIRT6), decreases expression of Insulin-like Growth Factor 1 (IGF-1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosters longevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging.
