Induction of Cellular Stress As a Potential Therapeutic Mechanism for Treatment of Autism

Background: Previous research has shown that symptoms of autism are reduced by fever. These functional improvements likely involve heat shock proteins and induction of cellular stress responses that lead to changes in synaptic function and increased long-range connectivity.

Objectives: Our aim has been to identify substances that activate cellular stress responses as possible therapeutic agents for the treatment of autism.

Methods: We investigated the effects of hydroxyurea (HU), 4-phenylbutyrate (4PBA) and trichostatin-A (TSA) on heat shock responses (HSR) and mitochondrial biogenesis in human fibroblasts with HU, 4PBA and TSA. mRNA expression of HSR genes (HSPA1A (HSP70), DNAJC3 (HSP40), and HSP90AA1 (HSP90)) were measured and analyzed by RT-PCR and plotted relative to untreated healthy transformed human fibroblasts after 6-24 hours of treatment. For mitochondrial mass, cells stained with Mitotracker Green FM, and Mitotracker Deep Red 633 or PBS as a negative control were subjected to flow cytometric analysis.

Results: HSP gene expression (relative maximum gene and protein expression) and mitochondrial mass are increased with respect to gene and protein expression, as well as mitochondrial mass in untreated fibroblasts for all 4 compounds (p<0.05).

Conclusions: This study demonstrates that it is possible to mimic the effects of fever in-vitro by activating HSR and increasing mitochondrial biogenesis. Of these, HU shows great potential since it is best characterized clinically and has alrready been clinically approved for other conditions. A clinical trial of HU in autism is in the planning stage and holds potential for treating core features of the disorder.