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The BDNF mimetic R-13 attenuates TBI pathogenesis using TrkB-related pathways and bioenergetics
R13, a small drug and BDNF mimetic showed promising results in improving spatial memory and anxiety-like behavior after TBI. Additionally, R13 was found to counteract reductions in molecules associated with BDNF signaling (p-TrkB, p-PI3K, p-AKT), synaptic plasticity (GluR2, PSD95, Synapsin I) as well as bioenergetic components such as mitophagy (SOD, PGC-1α, PINK1, Parkin, BNIP3, and LC3) and real- time mitochondrial respiratory capacity. Behavioral and molecular changes were accompanied by adaptations in functional connectivity assessed using MRI. Results highlight the potential of R13 as a therapeutic agent for TBI and provide valuable insights into the molecular and functional changes associated with brain injury.
Elucidation of the Role of Transient Receptor Potential (TRP) Channels in Cognitive Impairment using a Pharmacological Approach
This study investigated the involvement of TRPM2 and TRPV2 channels in diabetes- and beta-amyloid-induced cognitive impairment using a pharmacological inhibitor. In-vivo study, diabetic rats showed increased gene and protein expression of TRPV2 in the hippocampus of diabetes- and beta-amyloid-affected rats. The subsequent increase in the acetylcholinesterase activity in the cortex, as well as a decrease in the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also observed this led to the impairment in the learning and memory as evident from behavioral parameters such as Morris water maze test, passive avoidance and Y-maze test paradigm. Three-week treatment with tranilast (30 and 100 mg/kg, TRPV2 inhibitor) and 2-APB (3 and 10 mg/kg, TRPM2 inhibitor) showed improvement in learning and memory associated behaviours (Morris water maze test, passive avoidance, and Y-maze test) by increasing the p-CaMKII (Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and PSD-95 in the hippocampus. These findings depicted that TRP channel inhibition may be an effective treatment strategy for diabetes- and beta-amyloid-induced cognitive deficits.
Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders
TRP channel families include non-selective Ca2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels.
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