Ketamine preserves perineuronal nets in chronic stressed mice brain through the inhibition of microglia activation.

Schizophrenia is a severe neuropsychiatric disorder with positive, negative, and cognitive symptoms. Schizophrenia as a multi-dimensional disorder with a wide range of psychotic, negative, cognitive, mood, and motor dysfunctions (), has an overall prevalence of 5.03 per 1000 population (). Preclinical models of schizophrenia often use sub-chronic ketamine administration to induce schizophrenia-like model. For example, ketamine at the dose of 30 mg/kg for five consecutive days leads to the induction of schizophrenia-like model in male Wistar rats, showing hyperlocomotion, novel object memory deficit, and decreased pain threshold, although sex differences have been also shown (). The other study that uses the same protocol showed hyperlocomotion, novel object memory deficit, and decreased pain threshold with sex differences (). Other protocols use ketamine administration at the dose of 25 mg/kg and for 5–8 consecutive days (, ). Elevated locomotion and disrupted working memory are among the most deleterious effects of sub-chronic administration of ketamine in rodents (, , ). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that is affected in rodent models of schizophrenia. BDNF modulates neurotransmission, neuroplasticity, neurogenesis, and cognitive functions and the mood state. Evidence has shown the relationship between BDNF abnormalities and psychiatric disorders and cognitive disturbances in clinical and preclinical models (, , , , , , ). In rodent model of schizophrenia induced by ketamine, many studies have shown BDNF changes. Our recent works have revealed reduced BDNF levels in the prefrontal cortex of rats exposed to sub-chronic administration of ketamine (, ). Other study has shown BDNF downregulation in the hippocampus and the medial prefrontal cortex of rats received ketamine (). As mentioned, BDNF and other neurotrophins are involved in the growth and survival of neurons, and neurogenesis and synaptic plasticity. In the period of the brain development, different neurotrophic factors, particularly BDNF, potently promote neural growth and survival (). Also, axonal and dendrite growth, neurogenesis, neuroplasticity, and synaptic connections depend on neurotrophic factors (especially BDNF) function (, ). Importantly, BDNF is crucial for the function of dopaminergic, cholinergic, and serotonergic signaling, that are critically implicated in cognitive disturbances in schizophrenia (, ). Of note, models of drug-induced psychosis have shown that reduced BDNF concentration is associated with the induction of psychotic symptoms (, , ). Therefore, abnormalities in the function and the level of BDNF may underlie the pathophysiology of schizophrenia. On the other hand, Chlorogenic acid (CGA) may show neuroprotective effects. CGA family members are abundant dietary phenolic acid compounds in plants and have multiple protective effects such as anti-inflammation, antioxidation, and metabolic homeostasis modulation (, , ). CGA crosses the blood-brain barrier and induces neuroprotective effects in the brain (). CGA via induction of antioxidant and antiapoptotic properties can ameliorate cognitive impairments and improves mood disturbances (, , ). CGA also induces neuroprotective effects and improves learning and memory impairments (, ). The anti-anxiety and antidepressant effects of CGA have also been declared in previous research (, , ). CGA can suppress glutamate dehydrogenase (GDH) enzyme activity, the enzyme that is overactivated in schizophrenia (). However, there is no clear evidence in this regard. CGA serves as a neuroprotective agent via increasing the availability of BDNF in the frontal cortex and the dorsal striatum (). CGA also alleviates memory impairment induced by scopolamine by the increase of BDNF levels in mice (). Therefore, CGA may interfere with the pathophysiology of schizophrenia and may alter the function of BDNF, although evidence is so limited.