Exercise epigenetics is fueled by cell bioenergetics: Supporting role on brain plasticity and cognition.

Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

Humanin ameliorates TBI-related cognitive impairment by attenuating mitochondrial dysfunction and inflammation.

Traumatic brain injury (TBI) often results in a reduction of the capacity of cells to sustain energy demands, thus, compromising neuronal function and plasticity. Here we show that the mitochondrial activator humanin (HN) counteracts a TBI-related reduction in mitochondrial bioenergetics, including oxygen consumption rate. HN normalized the disruptive action of TBI on memory function, and restored levels of synaptic proteins (synapsin 1 and p-CREB). HN also counteracted TBI-related elevations of pro-inflammatory cytokines in plasma (TNF-α, INF-y, IL 17, IL 5, MCP 5, GCSF, RANNETS, sTNFRI) as well as in the hippocampus (gp-130 and p-STAT3). Gp-130 is an integral part of cytokine receptor impinging on STAT3 (Tyr-705) signaling. Furthermore, HN reduced astrocyte proliferation in TBI. The overall evidence suggests that HN plays an integral role in normalizing fundamental aspects of TBI pathology which are central to energy balance, brain function, and plasticity.

Altering the Trajectory of Perfusion-Diffusion Deficits Using A BDNF Mimetic Acutely After TBI is Associated with Improved Functional Connectivity.

Traumatic brain injury (TBI) results in metabolic deficits and functionally compromised tissue. The BDNF mimetic R13 has a significant positive effect on both tissue metabolism and behavioral outcome after TBI, indicating a promising therapeutic. To understand the mechanism of action for this intervention, we determined whether there was any association between the underlying metabolic insult and any improvement in resting state functional connectivity (FC) with MRI, or whether R13 acts through mechanisms unrelated to metabolic recovery. We found perfusion deficits could be reasonably approximated by reductions in mean diffusivity (MD) acutely after injury, because a majority of regions with low perfusion matched to regions of low MD, indicative of cell swelling. Injury alone resulted in reduced cross-brain FC and contralateral hyperconnectivity at 1d compared to sham and these were spatially coincident with regions of low MD. R13 intervention at 1-7d altered the tissue trajectory of MD pathology away from pseudo-normalization so that a greater volume of tissue remained with low MD at 7d. These same regions were associated with significant changes in cross-brain and contralateral FC in R13 treated rats compared to injured vehicle-treated rats. These data indicate a likely metabolic effect of R13 acutely after injury.

The BDNF mimetic R-13 attenuates TBI pathogenesis using TrkB-related pathways and bioenergetics.

Traumatic brain injury (TBI) is major neurological burden globally, and effective treatments are urgently needed. TBI is characterized by a reduction in energy metabolism and synaptic function that seems a primary cause of neuronal dysfunction. 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 this condition.

Pharmacological Modulation of TRPM2 Channels via PARP Pathway Leads to Neuroprotection in MPTP-induced Parkinson's Disease in Sprague Dawley Rats.

Transient receptor potential melastatin-2 (TRPM2) channels are cation channels activated by oxidative stress and ADP-ribose (ADPR). Role of TRPM2 channels has been postulated in several neurological disorders, but, it has not been explored in animal models of Parkinson's disease (PD). Thus, the role of TRPM2 and its associated poly (ADPR) polymerase (PARP) signaling pathways were investigated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model using TRPM2 inhibitor, 2-aminoethyl diphenyl borinate (2-APB), and PARP inhibitor, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34). PD was induced by using a bilateral intranigral administration of MPTP in rats, and different parameters were evaluated. An increase in oxidative stress was observed, leading to locomotor and cognitive deficits in the PD rats. PD rats also showed an increased TRPM2 expression in the striatum and mid-brain accompanied by reduced expression of tyrosine hydroxylase (TH) in comparison to sham animals. Intraperitoneal administration of 2-APB and PJ-34 led to an improvement in the locomotor and cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and an increase in TH levels in the striatum and mid-brain. In addition, these pharmacological interventions also led to a decrease in the expression of TRPM2 in PD in the striatum and mid-brain. Our results provide a rationale for the development of potent pharmacological agents targeting the TRPM2-PARP pathway to provide therapeutic benefits for the treatment of neurological diseases like PD.

Neuroprotective Effect of 2-Aminoethoxydiphenyl Borate (2-APB) in Amyloid ß-Induced Memory Dysfunction: A Mechanistic Study.

ß-Amyloid (Aß) peptide is a characteristic feature of Alzheimer's disease (AD) and accumulation of Aß is associated with loss of synaptic plasticity and neuronal cell death. Aggregation of Aß initiates numerous molecular signalling pathways leading to oxidative stress, mitochondrial dysfunction as well as an imbalance of calcium ion influx homeostasis. Recently, it has been shown that transient receptor potential melastatin 2 (TRPM2), a non-selective calcium-permeable cation channel has been postulated to play a vital role in the neuronal death, indicating the potential of TRPM2 inhibition in CNS disease. In this study, neuroprotective potential of 2-aminoethoxydiphenyl borate (2-APB), a broad-spectrum calcium channels blocker was investigated in Aß-induced memory deficits in rats. In addition, effect of 2-APB on TRPM2 channels gene and protein expressions and also on calcium and memory related proteins was investigated in the hippocampus. Intracerebroventricular (I.C.V.) administration of Aß (Aß25-35, 10 µg) markedly induced cognitive impairment and upregulation of mRNA and protein expression of TRPM2 in the hippocampus. In addition, AChE activity was also increased in the cortex of the Aß administered animals. Three-week treatment with 2-APB led to the down-regulation of TRPM2 mRNA and protein expression in the hippocampus and also improved the cognitive functions which was evident from the behavioral parameters. Moreover, 2-APB treatment also increased the calcium and memory associated proteins namely p-CaMKII, p-GSK-3ß, p-CREB and PSD-95 in the hippocampus and reduced the mRNA level of calcium buffering proteins and calcineurin A (PPP3CA) in the hippocampus. Furthermore, 2-APB treatment significantly reduced the AChE activity in the cortex. Thus, our findings suggest the neuroprotective effect of 2-APB in Aß-induced cognitive impairment.

Tranilast, a Transient Receptor Potential Vanilloid 2 Channel (TRPV2) Inhibitor Attenuates Amyloid ß-Induced Cognitive Impairment: Possible Mechanisms.

Alzheimer's disease (AD) is associated with the accumulation of ß-amyloid and leads to cognitive impairment. Numerous studies have established that neuronal calcium homeostasis is perturbed in AD. Recently, transient receptor potential vanilloid 2 (TRPV2) channels, a non-selective calcium-permeable channel, have been investigated in several diseases. However, the role of the TRPV2 channel has not been investigated in AD yet. In this study, intracerebroventricular administration of ß-amyloid (10 µg) to Sprague Dawley rats resulted in cognitive impairment which was evident from the assessment of cognitive tests. Also, TRPV2 mRNA and protein expression were found to be upregulated, while the expression of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), glycogen synthase kinase 3ß (p-GSK-3ß-Ser-9), cAMP response element-binding protein (p-CREB-Ser-133), and postsynaptic density protein 95 (PSD-95) were downregulated in the hippocampus of ß-amyloid-treated animals. Even, ß-amyloid-treated animals showed upregulation of mRNA level of calcium buffering proteins (parvalbumin and calsequestrin) and calcineurin A (PPP3CA) in the hippocampus. Acetylcholinesterase activity was also increased in the cortex of ß-amyloid-treated animals. Three-week treatment with tranilast showed improvement in the cognitive parameters which was associated with a decrease in TRPV2 expression and AChE activity. Additionally, an increase in the protein expression of p-CaMKII, p-GSK-3ß, p-CREB and PSD-95 in the hippocampus was found. Downregulation in the mRNA level of calcium buffering proteins (parvalbumin and calsequestrin) and calcineurin A in the hippocampus was also seen. These results reveal the importance of TRPV2 channels in the ß-amyloid-induced cognitive deficits and suggest TRPV2 as a potential target for AD.

Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders.

Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. 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.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study.

BACKGROUND: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. OBJECTIVE: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. METHODS: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. RESULTS: Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3ß-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3ß (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. CONCLUSION: This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.