In neurological diseases like diabetic neuropathy, Alzheimer’s disease, and schizophrenia, the expression of some genes such as caspase-3 and -9 and Bcl2 increases. Oxidative stress is one of the causes of Parkinson’s disease, multiple sclerosis, spongiform encephalopathy, Huntington’s disease, and amyotrophic lateral sclerosis. Silibinin, the powerful antioxidant without any side effects, can be used in treating of neurological diseases.

Ischemia-reperfusion injury (IRI) occurs in various organs in conditions that lead to blockage of arteries and disruption of blood flow to the tissue [1]. The severity of damage in different tissues varies depending on the type of cells and the oxygen saturation in their blood vessels. Some tissues and organs are more susceptible to IRI [1]. For example, the hepatocytes and neurons are more prone to ischemic damages because of their exclusive blood supply and slow repairing, respectively [2]. In the past, scientists believed that nerve cells could not be repaired or replaced, but now researchers found that nerve cells can be replaced after being damaged during re-emergence and cell renewal with a not fully understood mechanism [3-5]. Antioxidant and drug therapies are the two main choices to improve the IRI of neurons by reducing apoptosis and cell death [6]. Considering the recent research on drugs that lead to nerve cell repair and recognizing the repair pathways, silibinin, a powerful antioxidant, can be used simultaneously to affect the path of apoptosis. Silibinin significantly reduces the severity of IRI by modifying the expression of various genes that influence apoptosis and necrosis [7]. Diabetic neuropathy is one of the most common chronic and debilitating complications of diabetes. Elevated glucose increases the expression of caspases-3 and 9, which are involved in mitochondrial apoptosis [8]. The mechanism of glucose participating in apoptosis varies according to tissue and cell type. In the kidney, activating the caspase-9-dependent apoptosis pathway causes apoptosis of mesenteric cells and primary ganglion dorsal neurons [9]. We found that with the increase of cytochrome-C in mitochondria by ischemia-reperfusion, mitochondria can tolerate the high amount of cytochrome-C by boosting the expression of OPA1 and MFN1 genes. Silibinin lessened the amount of ROS, the expression of OPA1 and MFN1 genes, and mitochondrial fusion [10]. On the other hand, silibinin reduces the expression of BCL2, and as a result, the permeability of the mitochondrial membrane will not change. Thus, silibinin prevents the exit of cytochrome-C and the activation of caspase-3 and 9 [11]. Caspase-3 is one of the most impressive caspases in the breakdown of “amyloid beta-A4 precursor protein” (APP) associated with neuronal cell death in Alzheimer’s disease. Therefore, one of the effects of silibinin on Alzheimer’s can be the influence on the Bcl2 and caspase-3 [12,13]. Schizophrenia is a mental disorder characterized by abnormal behavior and reduced ability to perceive reality. The mechanism of schizophrenia has not yet been fully elucidated [14]. Bcl2 and caspase-3 gene expression increases in schizophrenia. Silibinin reduces caspase-3 and Bcl2, so it can also be effective in schizophrenia, which has not been studied before [15,16]. In a study conducted in 2020, silibinin increased serotonin and tryptophan hydroxylase-1 levels in the hippocampus. Silibinin could significantly reduce behavioral disorders, depression, fear, and also inhibited stress by lowering dopamine and increasing norepinephrine in the hippocampus [17]. It was shown that the expression of SNCA, PINK1, DJ1, ATP13A2, GIGYF2, and HTRA2 are involved in Parkinson’s disease. On the other hand, these genes are involved in the ubiquitin protein degradation pathway, oxidative stress response, cell survival, apoptosis, and mitochondrial function. So, one of the proposed treatments for Parkinson’s disease is a natural antioxidant like silibinin [18]. Recently, the evolution of oxidative stress was verified in different neurological clinics such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, spongiform encephalopathy, Huntington’s disease, and amyotrophic lateral sclerosis.

In conclusion, silibinin antioxidant potential, without any confirmed side effects, can be applied in the cure of neurological disease, with the support of more future investigations [19].