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

Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable. While the mechanisms and etiology of ASD are still unknown, a consensus is emerging about the synaptic nature of the syndrome, suggesting a possible avenue for pharmacological treatment with synaptogenic compounds. The peptidic mixture cerebrolysin (CBL) has been successfully used during the last three decades in the treatment of stroke and neurodegenerative disease. Animal experiments indicate that at least one possible mechanism of action of CBL is through neuroprotection and/or synaptogenesis. In the present study, we tested the effect of CBL treatment (daily injection of 2.5 mL/Kg i.p. during 15 days) on a rat model of ASD. This was based on the offspring (43 male and 51 female pups) of a pregnant female rat injected with valproic acid (VPA, 600 mg/Kg) at the embryonic day 12.5, which previous work has shown to display extensive behavioral, as well as synaptic impairment. Comparison between saline vs. CBL‐injected VPA animals shows that CBL treatment improves behavioral as well as synaptic impairments, measured by behavioral performance (social interaction, Y‐maze, plus‐maze), maximal response of inhibitory γ‐amino butyric acid type A receptor (GABAAR)‐mediated synaptic currents, as well as their kinetic properties and adrenergic and muscarinic modulation. We speculate that CBL might be a viable and effective candidate for pharmacological treatment or co‐treatment of ASD patients. © 2017 Wiley Periodicals, Inc.

[1]  H. Zemkova,et al.  Potentiation of GABAA receptor in cultured mouse hippocampal cells by brain-derived peptide mixture cerebrolysin. , 1995, Physiological research.

[2]  R. Hu Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) , 2003 .

[3]  V. Couceiro,et al.  Positive effects of Cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study , 2003, International clinical psychopharmacology.

[4]  N. Weinberger,et al.  Characterisation of multiple physiological fields within the anatomical core of rat auditory cortex , 2003, Hearing Research.

[5]  V. Couceiro,et al.  Positive effects of cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study. , 2003 .

[6]  Ryszard Przewłocki,et al.  Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism , 2005, Neuropsychopharmacology.

[7]  P. Hof,et al.  Autism: neuropathology, alterations of the GABAergic system, and animal models. , 2005, International review of neurobiology.

[8]  R. Przewłocki,et al.  Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism , 2006, Neuropsychopharmacology.

[9]  M. Atzori,et al.  Muscarinic M 2 and M 1 Receptors Reduce GABA Release by Ca 2 Channel Modulation Through Activation of PI 3 K / Ca 2-Independent and PLC / Ca 2-Dependent PKC , 2007 .

[10]  M. Atzori,et al.  Muscarinic M2 and M1 receptors reduce GABA release by Ca2+ channel modulation through activation of PI3K/Ca2+ -independent and PLC/Ca2+ -dependent PKC. , 2007, Journal of neurophysiology.

[11]  G. Blatt,et al.  Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study , 2009, Autism research : official journal of the International Society for Autism Research.

[12]  S. Gauthier,et al.  Cerebrolysin: a review of its use in dementia. , 2009, Drugs & aging.

[13]  S. Gauthier,et al.  Spotlight on Cerebrolysin in Dementia , 2010, CNS drugs.

[14]  T. Kemper,et al.  Parvalbumin‐, calbindin‐, and calretinin‐immunoreactive hippocampal interneuron density in autism , 2010, Acta neurologica Scandinavica.

[15]  J. Edgar,et al.  Validating γ Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism , 2010, Biological Psychiatry.

[16]  G. Blatt,et al.  Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism , 2011, Brain Research.

[17]  M. Atzori,et al.  Layer-specific noradrenergic modulation of inhibition in cortical layer II/III. , 2011, Cerebral cortex.

[18]  J. Matson,et al.  Issues in the Management of Challenging Behaviours of Adults with Autism Spectrum Disorder , 2011, CNS drugs.

[19]  G. Flores,et al.  The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice , 2011, Synapse.

[20]  E. Masliah,et al.  Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia , 2012, Journal of neuroscience research.

[21]  M. Atzori,et al.  Pre‐ and postsynaptic effects of norepinephrine on γ‐aminobutyric acid‐mediated synaptic transmission in layer 2/3 of the rat auditory cortex , 2012, Synapse.

[22]  A. Guekht,et al.  Cerebrolysin improves symptoms and delays progression in patients with Alzheimer's disease and vascular dementia. , 2012, Drugs of today.

[23]  N. Bornstein,et al.  Accelerated recovery from acute brain injuries: clinical efficacy of neurotrophic treatment in stroke and traumatic brain injuries. , 2012, Drugs of today.

[24]  M. Kilgard,et al.  Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. , 2013, The international journal of neuropsychopharmacology.

[25]  Giada Cellot,et al.  Reduced inhibitory gate in the barrel cortex of Neuroligin3R451C knock‐in mice, an animal model of autism spectrum disorders , 2014, Physiological reports.

[26]  M. Atzori,et al.  The Potential of Cerebrolysin in the Treatment of Schizophrenia , 2014 .

[27]  E. Klann,et al.  Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders , 2014, Science Signaling.

[28]  H. Anisman,et al.  Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: Similarities to autism spectrum disorders , 2014, Behavioural Brain Research.

[29]  F. Benfenati,et al.  Involvement of Synaptic Genes in the Pathogenesis of Autism Spectrum Disorders: The Case of Synapsins , 2014, Front. Pediatr..

[30]  M. Codagnone,et al.  Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism , 2015, Developmental Neuroscience.

[31]  E. Wynendaele,et al.  Peptide profiling of Internet-obtained Cerebrolysin using high performance liquid chromatography - electrospray ionization ion trap and ultra high performance liquid chromatography - ion mobility - quadrupole time of flight mass spectrometry. , 2015, Drug testing and analysis.

[32]  Sarah L. Logan,et al.  Aberrant Behaviors and Co-occurring Conditions as Predictors of Psychotropic Polypharmacy among Children with Autism Spectrum Disorders. , 2015, Journal of child and adolescent psychopharmacology.

[33]  R. Gao,et al.  Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. , 2015, Current molecular medicine.

[34]  M. Hotopf,et al.  Clinical predictors of antipsychotic use in children and adolescents with autism spectrum disorders: a historical open cohort study using electronic health records , 2015, European Child & Adolescent Psychiatry.

[35]  K. Bahali,et al.  A Retrospective Investigation of Clozapine Treatment in Autistic and Nonautistic Children and Adolescents in an Inpatient Clinic in Turkey. , 2016, Journal of child and adolescent psychopharmacology.

[36]  Michael S. C. Thomas,et al.  The over-pruning hypothesis of autism. , 2016, Developmental science.

[37]  Bhupesh Sharma,et al.  Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats , 2016, Brain Research Bulletin.

[38]  L. Ziganshina,et al.  Cerebrolysin for acute ischaemic stroke. , 2016, The Cochrane database of systematic reviews.

[39]  Marc V. Fuccillo,et al.  Striatal Circuits as a Common Node for Autism Pathophysiology , 2016, Front. Neurosci..

[40]  S. White,et al.  Long-Term Effects of CBT on Social Impairment in Adolescents with ASD , 2017, Journal of autism and developmental disorders.

[41]  Jing Tao,et al.  Gastrodin Rescues Autistic-Like Phenotypes in Valproic Acid-Induced Animal Model , 2018, Front. Neurol..