Developmental neurotoxicity

Developmental neurotoxicity, olfactory toxicity and intranasal delivery of therapeutic agents to the brain  (Eva Brittebo) 

Exposure to environmental pollutants during early life has recently been suggested as a potential risk factor for sporadic forms of neurodegenerative disease. We have identified a cyanobacterial neurotoxin BMAA (β-N-methylamino-L-alanine) that induces specific long-term degenerative changes in the rodent hippocampus following neonatal exposure. Cognitive deficits as well as progressive neurodegenerative changes including abundant intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins were observed in the adult rat hippocampus. 

We have also identified some potent olfactory toxicants (e.g. the herbicides chlorthiamid and its major metabolite dichobenil as well as 2,6-dichlorophenyl methylsulfone). These compounds induce extensive necrosis in the olfactory mucosa and permanent degenerative changes in the olfactory region following a CYP-dependent bioactivation to reactive intermediates. There is also an activation of stress proteins and caspases in the olfactory mucosa. In addition, a CYP-dependent bioactivation of the antithyroid drug methimazole was demonstrated to induce an extensive but reversible toxicity in the olfactory mucosa as well as secondary changes in the olfactory bulb.

Finally, we have demonstrated that intranasal delivery of novel cell-based therapeutic agents such as engineered T regulatory (Treg) cells and CNS retargeted human mesenchymal stromal cells (MSC) parentes will significantly suppress ongoing inflammation and reduce disease symptoms in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.