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Advanced Neurology TRPM2 in neurological disorders

Emptying of lysosomal Ca stores suppresses adenosine the underlying pathology, and may only approximate the
2+
diphosphate ribose (ADPR)-mediated Ca release, late state of the disease . Consequently, alternative genetic
[37]
2+
indicating that ADPR-dependent TRPM2 channels models have been explored, such as transgenic mice with
function as lysosomal Ca channels . Cytoplasmic alterations to the α-synuclein gene .
[7]
[37]
2+
distribution of TRPM2 has also been observed in dendritic The interaction between oxidative stress and PD
cells, with TRPM2 mostly localized on the lysosomal means that understanding the molecular mechanisms
membrane. Furthermore, TRPM2-deficient dendritic cells and proteins that contribute to ROS-induced cellular
exhibit impaired chemotaxis in response to chemokine dysfunction is important in developing therapeutics.
stimulation . These findings highlight the importance ROS induces TRPM2 channel activation through the
[35]
of TRPM2 in responding to both extracellular and generation of ADPR in the cell nucleus ; therefore,
[40]
intracellular perturbations . TRPM2 activation may play a role in PD. In microglial
[35]
3. TRPM2 in neurological disease and acute cells, TRPM2 activation leads to the production of pro-
brain injury inflammatory mediators that contribute to reduced blood
flow and hypoxic-ischemic injury, neuropathic pain, and
3.1. PD neurodegeneration . TRPM2 is also localized in the cell
[40]
PD is a neurodegenerative disorder encompassing a membrane of dopaminergic neurons in the rat substantia
range of motor and non-motor deficits, such as resting nigra and is activated in response to H O , which indicates
2
2
[25]
[36]
tremor and cognitive changes . Numerous risk factors a possible contribution of TRPM2 to PD pathology .
including mitochondrial dysfunction and inflammation There are indicators of a TRPM2 contribution to PD
are associated with PD pathology and contribute to its progression. Amyotrophic lateral sclerosis and PD share
progression . overlapping symptoms and occur at a relatively high rate
[36]
[41]
Animal and cell models have been developed to on three separate Western Pacific islands . Hermosura
simulate features of PD. Commonly used models involve et al. identified in a Guamanian population a variant in
administering toxins to animals or cell cultures, such as the TRPM2 channel that increases susceptibility to PD and
[42]
6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl- amyotrophic lateral sclerosis . This variant is a missense
[42]
1,2,3,6-tetrahydropyridine (MPTP). 6-OHDA needs mutation that inactivates the channel .
to be injected into the brain because it does not cross In an MPTP-induced PD rat model, administration of
the BBB, and it leads to degeneration of dopaminergic 2-APB (a TRPM2 and general Ca channel blocker) and
2+
neurons in regions such as the striatum, medial forebrain PJ-34 (a PARP inhibitor that impairs TRPM2 function)
bundle, and substantia nigra . The mechanism of action improved cognition and locomotion, with decreased
[37]
underlying this effect is likely through auto-oxidation of TRPM2 levels in the striatum and midbrain in the PD
6-OHDA leading to H O , superoxide radicals, and ROS rat . In a 6-OHDA rat model, TRPM2 was upregulated in
[43]
2
2
production . MPTP crosses the BBB and is converted the substantia nigra . When dorsal root ganglion neurons
[44]
[37]
to 1-methyl-4-phenylpyridinium ions (MPP ) that are were isolated from a rat and exposed to rotenone, TRPM2
+
taken up by dopaminergic neurons through dopamine currents, which were blocked by TRPM2 inhibitors, were
transporters (DATs) . This leads to the inhibition of the generated .
[38]
[45]
electron transport chain (ETC), decreased mitochondrial Further support for the involvement of TRPM2 in
membrane potential, and altered calcium homeostasis, PD has been demonstrated in cell culture studies. The
ultimately leading to neuronal death . neuroblastoma SH-SY5Y cell line is often used in these
[38]
An important mechanism of MPTP-generated studies because these cells are of human origin and are easy
[39]
neurotoxicity is oxidative stress . MPTP accumulation to maintain. In addition, they possess catecholaminergic
in dopaminergic neurons generates ROS through properties, such as the ability to produce dopamine .
[46]
the mitochondria . These species may damage cells In PD patients administered with dopamine synthesis-
[39]
through reactions that lead to lipid peroxidation, DNA enhancing drugs, homocysteine is produced as a
damage, changes to membrane fluidity, and endothelial byproduct, which may cause side effects, such as apoptosis
dysfunction [38,39] . Molecules with similar structures to and oxidative stress, contributing to PD development .
[47]
MPTP, such as rotenone (insecticide) and paraquat (a This is replicated in SH-SY5Y cells exposed to MPP
+
herbicide), also induce degeneration of dopaminergic and homocysteine, which display high levels of ROS,
neurons . Neurotoxin models are relatively simple, mitochondrial membrane depolarization, and activation
[39]
merely requiring an injection of the substance. However, of caspases (enzymes involved in apoptosis) . This effect
[47]
such models only mimic pathological symptoms and not was reduced by selenium, an antioxidant, and 2-APB,
Volume 1 Issue 1 (2022) 4 https://doi.org/10.36922/an.v1i1.3