Cerebrolysin prevents deficits in social behavior, repetitive conduct, and synaptic inhibition in a rat model of autism

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Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental conditions characterized by repetitive or obsessive behavior, and impaired communication and social conduct (Frances, et al., 2000). The number of ASD incidence repeated in the last decade has increased dramatically from 0.7% (∼ 1/150) to 1.5% (∼ 1/68; CDC, 2016). ASD can be extremely incapacitating, exerting a heavy burden on the patients, their families, and the society at large.
Since ASD etiology is still largely unknown, and the syndrome can only be diagnosed during early childhood, it is of paramount importance to identify effective and accessible treatment to relieve families and patients alike from at least part of its incapacitating effects. Progress in ASD early detection have made possible the use of cognitive behavioral therapy (CBT) for the partial recovery of ASD symptoms (Maddox et al., 2016). Yet, in many circumstances, alternative or additional therapy may be desirable for ASD patients.
It is unfortunate that there are no drugs Currently, there are no mechanistic treatments or cure available for ASD patients. Among the drugs used for treating ASD symptoms are second generation antipsychotics (Downs et al., 2015), antidepressants, and drugs approved for the treatment of attention deficit disorders (Logan et al., 2015). Prescription of these drugs is typically meant for symptomatic and acute treatment of ASD symptoms, without actually treating the underlying disorder. Moreover, their prolonged use often comes with a barrage of disturbing side‐effects which severely limits their clinical efficacy (Matson et al., 2011; Yalcin et al., 2016). For all these reasons there is a strong unmet need for effective pharmacological treatment of ASD.
Converging evidence from clinics (Santini and Klann, 2014; Gao and Penzes, 2015; Thomas et al., 2016) as well as animal models (Giovedí et al., 2014; Santini and Klann, 2014), suggests that ASD is associated with a variety of synaptic alterations of either or both the excitatory of the inhibitory system in critical areas of the brain controlling communication, social behavior and movement (Codagnone et al., 2015), as well as movement (Fuccillo, 2016).
Work from several groups, including our own, suggests that inhibitory synapses mediated by the neurotransmitter γ‐amino butyric acid (GABA) are severely impaired in human ASD patients as well as in other ASD animal models (Schmitz et al., 2005; Yip et al., 2009; Lawrence et al., 2010; Oblak et al., 2011; Banerjee et al., 2013; Cellot and Cherubini, 2014).
Cerebrolysin (CBL) is an amino acid/peptide mixture (Gevaert et al., 2015) that has been successfully used to promote synaptic growth in the treatment of cerebral stroke (Bornstein and Poon, 2012), Alzheimer's disease (Allegri and Guekht, 2012), traumatic brain injury (Bornstein and Poon, 2012), and neurodevelopmental disorders, including schizophrenia (Flores and Atzori, 2014). In particular, CBL has been shown to potentiate GABAA‐receptor‐mediated responses in mouse hippocampal cell cultures (Zemkova et al., 1995).
For all these reasons, we tested the efficacy of CBL in relieving ASD symptoms in a rodent model of ASD (Schneider and Przewlocki, 2005; Schneider et al., 2006). Previous studies have shown that the offspring of mothers injected with VPA during pregnancy display a set of symptoms analogous to human ASD, including impairments in communication and social behavior and increased repetitive conduct. Our results suggest that early CBL treatment improves—at least in part—the behavioral deficits and prevents the impairment of GABAergic synapses of VPA offspring.
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