Glimepiride reproduces its magical effect! Can it actually reduce tau lesions and neuroinflammation?

Background: Tau protein is the main microtubule-related protein (encoded by genes) in the mammalian nervous system, which plays many important roles
in maintaining nerve cell function and structure in its physiological state.
Tau function is adversely affected by many post-translational modifications, including phosphorylation, acetylation and ubiquitination
.
Phosphorylation and dephosphorylation processes control the stability
of the microtubule cytoskeleton.
In this system, an imbalance between kinase and phosphatase activity leads to increased
microtubule-associated Tau hyperphosphorylation and apoptosis.
In addition, it causes intracellular neurofibribrillary tangles (NFT) aggregation, an important aspect of
Alzheimer's disease (AD) pathology.
In addition, acetylation has been identified as a toxic post-translational modification
of tau proteins in the brains of AD patients and associated tau proteinopathy patients.
Tau acetylation reduces the binding of tau to microtubules, inhibits microtubule stabilization, enhances tau fibrillation, reduces tau degradation, and leads to tau-mediated synaptic toxicity
.
Tau disease is used to describe the pathogenesis of all diseases
associated with tau protein.
A variety of neurodegenerative diseases, such as AD, progressive supranuclear palsy (PSP), frontotemporal degeneration (FTLD), and parkinsonism, are characterized by the aggregation of tau inclusions
within neurons caused by abnormal post-translational modifications of tau protein, such as hyperphosphorylation and acetylation.

To mimic neurodegenerative tau proteinopathy, several transgenic mouse strains that overexpress human tau protein and have mutations in the MAPT gene have been developed, including P301S
.
P301S transgenic mice have a mutation in exon 10 that results in proline at position 301 being replaced
by serine.
These mice exhibit synaptic pathology at 3 months of age, filamentous tau injury, sports injury, neurodegeneration, microglial activation at 6 months of age, and present clinical phenotypes
(PSP) and (FTLD).
These mice are also an interesting model to study the spread of tau hyperphosphorylation and abnormal tau in the brain and spinal cord

Numerous studies have shown a strong link
between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease.
In fact, cerebral insulin resistance may represent a bridge to neurodegenerative diseases, with implications
for learning, synaptic plasticity, and memory.
In T2D, insulin resistance and hyperglycemia can lead to overphosphorylation of
the Tau protein.
Therefore, looking for a drug with dual therapeutic activity against T2D and neuroprotection would be a promising idea
.

Glimepiride (GPD) is an oral anti-diabetic drug classified as a third-generation sulfonylurea (SU) that stimulates insulin secretion
by binding to sulfonylurea receptors (SUR1) on the cell membrane of the pancreas.
GPD is well tolerated and has been tested for safety in many randomized clinical trials, reducing the risk of hypoglycemia and weight gain
.
In addition to these pancreatic effects, it has been reported to have additional pancreatic effects, such as improving insulin resistance and protecting hippocampal and cortical neurons from the toxic effects
of the prion-derived peptide PrP82-146.
GPD has been reported to reduce the production
of β amyloid by inhibiting the activity of the BACE1 enzyme in primary cortical neurons.
GPD protects neurons from amyloid-induced synaptic damage
β.
GPD has been reported to dock with PPARγ and exhibit PPARγ agonistic activity
in cell-based transactivation assays.
In addition, GPD has shown dose-dependent inhibitory activity
against acetylcholinesterase by molecular docking.

Objective: To investigate the potential neuroprotective effects and possible neuroprotective mechanisms
of GPD on tau lesions and neuroinflammation using a P301S transgenic mouse model considering the link between T2D and neurodegenerative diseases.

Methods: P301S mouse model was used as tau disease model, and C57BL/6 wild-type mouse was used as control
.
Levels of phosphorylated and acetylated tau proteins in the cortex and hippocampus are assessed by western blotting
.
To assess the effects of
GPD on enzymes, neuroinflammation, and apoptosis markers associated with tau lesions.
In addition, neuroprotective effects
on anxiety-like behavior and sports injuries were analyzed using parallel pole floors and open field trials.

Results: GPD significantly improved dyskinesia, anxiety-like behavior and neurodegeneration in P301S mice
.
By decreasing GSK3β, increasing the ratio of phosphorylated-AKT to total-AKT, increasing PP2A, and normalizing CDK5 levels, phosphorylated tau and acetylated tau were significantly reduced
in the cortex and hippocampus of P301S mice.
In addition, GPD treatment also reduces neuroinflammation and apoptosis
by reducing NF-kB, TNF-α, and caspase 3 levels.

Figure 1 Study timeline for GPD administration days during the screening phase and subsequent mechanical phases

Figure 2 Broadfield neurobehavioral test results
.
To study the effects of 21-day doses (1, 2, 4 mg/kg) of GPD therapy on different parameters; A total distance traveled (m), b maximum speed (msec 1), c time in the center area (seconds), d time in corner area (seconds).

Data are expressed
as mean ± standard deviation (n = 8).
The statistical analysis uses one-way ANOVA followed by a Tukey post-hoc test
.
*、#P301SWT(P < 0.
05)

Figure 3 Neurobehavioral test results
.
Study on the effect of GPD dose (1, 2, 4 mg/kg) on different parameters for 21 days: number of foot slides, total walking distance (m), animal body rotation, number of times d crossing the line
.
Data are expressed
as mean ± standard deviation (n=8).
The statistical analysis used one-way ANOVA followed by Tukey's posttest
.
*、#P301SWT(P<0.
05)

Fig.
4 Effect of GPD treatment on neurodegenerative changes induced by tau disease, represented by micrographs of Niech blue-stained hippocampal and cortical slices in p301S and WT treated with GPD for 21 days; Micrograph showing Nikess particles (black arrows) with significantly reduced density and distribution in vehicle-treated p301s mice and increased in GPD treatment (400x scale bar = 50 μm); Quantification of Nikit in the cerebral cortex by Image J software, Nikit in hippocampal CA by Image J software, and Quantification of Nikit in the DG region by Image J software, significantly reduced
Nikarchite in the DG region compared to the WT group and p301S mice receiving (1, 2,4 mg/kg) GPD 。 At the same time, the number of Nikelli-positive cells in the cerebral cortex, hippocampal CA, and DG regions was significantly increased
in p301s mice receiving (1, 2, 4 mg/kg) GPD, especially in the p301s group receiving (4 mg/kg) GPD.
Data are expressed
as mean ± standard deviation (n = 10).
The statistical analysis uses one-way ANOVA followed by a Tukey post-hoc test
.
*, #: Statistical significance from P301S and WT groups (P < 0.
05), respectively

Figure 5 is a micrograph of a brain slice stained with Congo red, showing the presence of positive red-stained β-amyloid (400-fold scale bar = 50 μm) in vehicle-treated P301S mice and P301S mice receiving (1,2 mg/kg) GPD for 21 days; Quantitative analysis of the number of plaques by Image J software showed that plaques were absent in P301S treated with (4 mg/kg) GPD compared to the P301S group treated with excipients and significantly less
in the cortex of the P301S group receiving (1,2 mg/kg) GPD.
Data are expressed
as mean ± standard deviation (n = 10).
The statistical analysis uses one-way ANOVA followed by a Tukey post-hoc test
.
*、#P301SWT(P < 0.
05)

Conclusions: Current data suggest that GPD has a protective effect
against amyotrophic lateral sclerosis, behavioral consequences, neurodegeneration, neuroinflammation and apoptosis.
Therefore, GPD is a promising drug
for the treatment of neurodegenerative diseases associated with neurodegenerative diseases.

Original source: Zaki MO, El-Desouky S, Elsherbiny DA, et al.
Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3β signaling.
Inflammopharmacology 2022 Oct; 30(5)