Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia

Abstract

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.

Intranasal Delivery of Mesenchymal Stem Cells-Derived Extracellular Vesicles for the Treatment of Neurological Diseases

“…In addition, there was also an improvement in schizophrenic behaviors such as social interactions and disruption in prepulse inhibition. EVs were able to migrate and localize in the prefrontal cortex of treated mice, which is a crucial region involved in the pathogenicity of schizophrenia 49 . These results indicate that treatment with EVs can prevent or ameliorate symptoms of neurodevelopmental disorders in animal models, with the therapeutic potential to activate molecular and protein changes in the neurons.…”

“…IN administration of EVs provides an effective strategy to treat a variety of CNS pathologies, including neurodegenerative diseases such as Parkinson's disease (PD), 44 MS, 34 and Alzheimer's disease (AD), 45‐47 psychiatric disorders including autism 32,48 and schizophrenia, 49 and neurotrauma such as that caused by perinatal brain injury, 50 status epilepticus (SE), 42,51 and traumatic brain damage (TBI) 52 …”

“…In a mice model of Alzheimer's disease, it was shown that the majority of PKH‐labeled MSC‐derived EVs delivered IN, could be seen to accumulate in the layer of immature olfactory sensory neurons 49 . EVs were observed to pass through the cribriform plate, concentrate in the glomerulus, and then progress to the next grade nerve cells, the mitral cells, before being transported further to other brain areas 47 .…”

Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders

“…Beneficial effects of intranasally injected MSC-Exos in the improvement of cognitive function were observed in phencyclidine (PCP)-treated mice, a well-established murine model of schizophrenia [ 51 ]. Tsivion-Visbord and colleagues demonstrated that intranasal delivery of MSC-Exos managed to alleviate schizophrenia-like behaviors by preserving viability of Gamma aminobutyric acid (GABA)-producing neurons and by modulating activity of neurotransmitters in the CNS [ 51 ]. Immediately after injection, the majority of MSC-Exos accumulated in the neurons of the prefrontal cortex (PFC), the brain area that is the most severely affected in schizophrenia.…”

“…Significantly reduced glutamate levels in the cerebrospinal fluid and a remarkably increased number of GABA-producing neurons were observed in PFC of PCP-treated mice that received MSC-Exos. Importantly, MSC-Exos improved social interaction and disruption in prepulse inhibition in PCP-treated mice, significantly attenuating schizophrenia-like behavior [ 51 ]. Since no negative symptoms were detected following intranasal administration of MSC-Exos in mice [ 50 , 51 ], efficacy of this non-invasive therapeutic approach should be further explored in upcoming clinical studies for the amelioration of behavioral symptoms in patients suffering from schizophrenia and ASD.…”