Evaluation of the potential neuroprotective effects of (R)-(-)-Linalool: in vitro and in vivo studies

Multiple sclerosis (MS) is defined as a chronic, autoimmune, neurodegenerative, demyelinating, and inflammatory disorder of the central nervous system (CNS)1, causing motor, cognitive and sensory deficits2. It affects 2.9 million people worldwide, with the highest incidence rates in Sardinia4. This study evaluated (R)-(-)-Linalool (LIN) as a potential treatment for MS, considering the anti-inflammatory, antioxidant and neuroprotective effects previously reported5,6,7. In vitro experiments on female and male human umbilical vein endothelial cells exposed to lipopolysaccharide indicated that LIN may act as a neuroprotective, antioxidant and anti-inflammatory compound, with a sex-dependent mechanism of action, highlighting its relevance in disorders characterized by endothelial dysfunction, such as neurodegenerative diseases. Based on previous evidences2, in vivo experiments were conducted on male and female Wistar rats administered with cuprizone, to reproduce an animal model of MS, and treated with LIN. Long-term treatment with cuprizone induced cognitive deficits associated with altered mesocortical dopaminergic function, whereas short-term treatment restored both cognitive deficits and DA extracellular levels. LIN did not induce a protective effect on cuprizone-induced cognitive deficits, with no sex differences; but restored the reduced dopaminergic turnover in homogenates of PFCx but not of striatum, with sex differences. Furthermore, cuprizone-treated animals displayed reduced anxiety-like behavior, which was attenuated after LIN treatment, in males but not in females. LIN also appeared to prevent changes in motor impairments induced by cuprizone treatment, with sex differences. The results obtained provide a rationale for expanding our understanding of the mechanisms underlying the pathology and support a potential pharmacological approach for the disease.