New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis

Abstract

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway.

The Psychonauts’ World of Cognitive Enhancers

“…Piracetam enhances cognitive function without causing sedation or stimulation ( 3 ). This drug is also being used in clinical practice for the treatment of several diseases ( 59 – 62 ) although its mechanism of action remains not fully understood.…”

The use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?

“…Similarly, short treatment with CA has increased the expression of synaptic, mitochondrial, and antioxidant response genes and improved different domains of cognitive performance (executive function, memory, and learning) in 5xFAD animals as well as reduced the burden of Aβ plaque burden in the hippocampus 54 . Lipopolysaccharide (LPS) induced oxidative stress, cell death and inflammatory response in Sprague Dawley rats were reversed by piracetam through attenuation against mitochondria-mediated caspase-independent pathway 55 . A new Tacrine-Hydroxyphenylbenzimidazole (TAC-BIM) hybrid compound with excellent multifunctional activity was developed and tested on Human neuroblastoma SH-SY5Y Cell lines.…”

Cardinal role of eukaryotic initiation factor 2 (eIF2α) in neuronal death : implication of PERK:IRE1α:ATF6 axis in Parkinson’s pathology

“…Rotenone is a natural product extracted from the seeds and stems of several plants and primarily involve the impaired mitochondrial complex-I activity and depleted ATP level for neuronal death (Zhang et al, 2013). Studies from our lab and other's have showed the involvement of oxidative stress and nitrosative stress in rotenone administered rat brain in various rat brain regions (Khadrawy et al, 2017;Verma et al, 2018;Swarnkar et al, 2010). It has also been reported that rotenone administration in rat brain caused the altered behavioral, pathological and biochemical parameters (Swarnkar et al, 2010;.…”

“…Total RNA was extracted from brain regions by trizol reagent based on the manufacturer guidelines and reported previously (Verma et al, 2018). The amplified PCR products were observed by electrophoresis using 2% agarose gel imaged by gel documentation system.…”

“…ROS level was estimated according to method described by Verma et al, (2018) and signals were recordede by fluorimeter (Varian Cary Eclipse, USA) at excitation of 485 nm and emission at 525 nm wavelengths.…”