Ion Channels and Metal Ions in Parkinson's Disease: Historical Perspective to the Current Scenario.

Parkinson's disease (PD) is a neurodegenerative condition linked to the deterioration of motor and cognitive performance. It produces degeneration of the dopaminergic neurons along the nigrostriatal pathway in the central nervous system (CNS), which leads to symptoms such as bradykinesias, tremors, rigidity, and postural instability. There are several medications currently approved for the therapy of PD, but a permanent cure for it remains elusive. With the aging population set to increase, a number of PD cases are expected to shoot up in the coming times. Hence, there is a need to look for new molecular targets that could be investigated both preclinically and clinically for PD treatment. Among these, several ion channels and metal ions are being studied for their effects on PD pathology and the functioning of dopaminergic neurons. Ion channels such as N-methyl-D-aspartate (NMDA), γ-aminobutyric acid A (GABAA), voltage-gated calcium channels, potassium channels, HCN channels, Hv1 proton channels, and voltage-gated sodium channels and metal ions such as mercury, zinc, copper, iron, manganese, calcium, and lead showed prominent involvement in PD. Pharmacological agents have been used to target these ion channels and metal ions to prevent or treat PD. Hence, in the present review, we summarize the pathophysiological events linked to PD with an emphasis on the role of ions and ion channels in PD pathology, and pharmacological agents targeting these ion channels have also been listed.

2-Aminoethoxydiphenyl borate ameliorates mitochondrial dysfunctions in MPTP/MPP+ model of Parkinson's disease.

Mitochondrial dysfunction is closely linked with the pathophysiology of several neurodegenerative disorders including Parkinson's disease (PD). Despite several therapeutic advancements related to symptomatic modification of PD pathology, strategies targeting mitochondrial dysfunctions remain largely elusive. Recently, transient receptor potential (TRP) channels have been shown to play a pivotal role in the control of mitochondrial and neuronal functioning in PD. In this study, the effect of 2-aminoethoxydiphenyl borate (2-APB), TRP channel blocker was investigated in the context of mitochondrial dysfunctions in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administered Sprague Dawley rats. MPP+-treated SH-SY5Y cells exhibited reductions in cell viability, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Co-treatment with 2-APB led to an increase in cell viability, reduction in intracellular and mitochondrial ROS and improvement in mitochondrial membrane potential compared to MPP+-treated SH-SY5Y cells. In addition, intranigral administration of MPTP led to a significant reduction in motor function in the rats. Fourteen days of 2-APB (3 and 10 mg/kg, i.p.) treatment improved behavioural parameters. MPTP-induced decrease in complex I activity and mitochondrial potential were also blocked by 2-APB in the mitochondria isolated from the brain regions i.e. midbrain and striatum. MPTP-induced decrease in tyrosine hydroxylase levels were also restored by 2-APB. Moreover, MPTP-induced reduction in proteins involved in mitochondrial biogenesis, viz. peroxisome proliferator-activated-receptor-gamma coactivator and mitochondrial transcription factor-A were increased after 2-APB treatment in vivo. In summary, 2-APB has a promising neuroprotective role in the MPP+/MPTP models of PD via targeting mitochondrial dysfunctions and biogenesis.

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.

Hyper-insulinemia increases the glutamate-excitotoxicity in cortical neurons: A mechanistic study.

Insulin resistance in type-2 diabetic condition increases the risk of stroke and cognitive deficits in which involvement of glutamate has been postulated. It has been hypothesized that hyper-insulinemia in cortical neurons increases the vulnerability towards glutamate-induced excitotoxicity. To mimic insulin resistance, cortical neurons were incubated with high insulin (1 µM) and high glucose (50 mM final concentration) in in-vitro condition for 24 h. Pre-treatment of cortical neurons with high insulin blocked acute insulin-induced activation of Akt and GSK-3ß but not in the case of high glucose. Our results demonstrate that chronic high insulin exposure increases glutamate-induced excitotoxity, which was blocked by insulin receptor antagonist (S961) and GSK-3ß inhibitor (SB216763). These inhibitors also ameliorated pAkt (Ser473) and pGSK-3ß(Ser9) levels after chronic insulin exposure. Increase in glutamate-excitotoxicity in insulin-resistant cortical neurons was found to be associated with increased expression of PICK1. However, GluR2 did not get altered in hyper-insulinemia condition. This study demonstrates that hyper-insulinemia increases glutamate excitotoxicity which could be attributed to activation of GSK-3ß and increased expression of PICK1.

Effects of 4-phenyl butyric acid on high glucose-induced alterations in dorsal root ganglion neurons.

Mechanisms and pathways involving in diabetic neuropathy are still not fully understood but can be unified by the process of overproduction of reactive oxygen species (ROS) such as superoxide, endoplasmic reticulum (ER) stress, downstream intracellular signaling pathways and their modulation. Susceptibility of dorsal root ganglion (DRG) to internal/external hyperglycemic environment stress contributes to the pathogenesis and progression of diabetic neuropathy. ER stress leads to abnormal ion channel function, gene expression, transcriptional regulation, metabolism and protein folding. 4-phenyl butyric acid (4-PBA) is a potent and selective chemical chaperone; which may inhibit ER stress. It may be hypothesized that 4-PBA could attenuate via channels in DRG in diabetic neuropathy. Effects of 4-PBA were determined by applying different parameters of oxidative stress, cell viability, apoptosis assays and channel expression in cultured DRG neurons. Hyperglycemia-induced apoptosis in the DRG neuron was inhibited by 4-PBA. Cell viability of DRG neurons was not altered by 4-PBA. Oxidative stress was significantly blocked by the 4-PBA. Sodium channel expression was not altered by the 4-PBA. Our data provide evidence that the hyperglycemia-induced alteration may be reduced by the 4-PBA without altering the sodium channel expression.

Diabetic-induced increased sodium channel activity attenuated by tetracaine in sensory neurons in vitro.

The present study was aimed to explore correlation between the altered pain perception and Na(+) channel activity in diabetic animals as well as the effect of tetracaine on sensory neurons of diabetic rat. In streptozotocin-induced diabetic rats behavioral nociceptive parameters were assessed. The Na(+) current (INa) was obtained using whole-cell voltage-clamp configuration in dorsal root ganglion (DRG) neurons isolated from diabetic rat (in vitro). In addition, the effects of tetracaine on altered Na(+) channel activity associated with diabetes in small DRG neurons were evaluated. After induction of diabetes mechanical allodynia, thermal hyperalgesia and Na(+) channel activity were altered significantly in 4th and 6th week in relation to the control. Altered pain parameters were in correlation with increased INa in time-dependent manner. In comparison to age-matched control (-1.10±0.20nA) the INa was found to be -2.49±0.21nA at 4th week and -3.71±0.28nA at 6th week. The increased activity of Na(+) channels was blocked by tetracaine even in diabetic condition. The depression of the INa on tetracaine exposure was not sensitive to the voltage or time. The conductance curve shifted towards right around -8.0mV. The alterations in neuropathic pain associated with diabetes and Na(+) channel activity has been clearly correlated in time-dependent manner. The INa density was increased significantly with the progression of neuropathic pain. Local anesthetic, tetracaine potentially blocked the Na(+) channel activity in diabetic sensory neurons.

Neuropharmacological profile of L-pGlu-(1-benzyl)-L-His-L-ProNH2, a newer thyrotropin-releasing hormone analog: effects on seizure models, sodium current, cerebral blood flow and behavioral parameters.

In the present study, L-pGlu-(1-benzyl)-L-His-L-ProNH(2) (NP-355), a newer CNS active thyrotropin-releasing hormone (TRH) analog was evaluated for its antiepileptic potential. NP-355 (5, 10 and 20 micromol/kg; i.v.) pretreatment significantly delayed onset and reduced the frequency of convulsions in pentylenetetrazole-induced seizures. NP-355 was also found to be protective against picrotoxin- and kainic acid-induced seizures. Maximum electroshock-induced seizures were not protected even at 20 micromol/kg in mice. Effects of NP-355 on functional observation battery did not exhibit any undesirable effects. Moreover, the antiepileptic activity produced by NP-355 was observed without significantly altering mean arterial blood pressure. NP-355 significantly increases the CBF to 17+/-3% as compared to saline (6+/-2%). NP-355 (100, 300 and 1000 microM) produces a concentration-dependent depression (16%, 63% and 77%, respectively) of the peak sodium current. NP-355 did not alter neurobehavioral parameters. This study demonstrates that NP-355 has potential antiepileptic activity and devoid of undesirable effects.