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Brain cells transformed into zombie-like states may play a role in the onset of epilepsy, according to the results of a recent study.(Image credit: John M Lund Photography Inc/Getty Images)ShareShare by:
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Eliminating “undead” cells within the brain may offer relief for a prevalent form of epilepsy, indicates a fresh investigation performed in the laboratory.
Within this investigation, documented in the Annals of Neurology journal, scientists reported that the elimination of harmed-but-immortal brain cells within mice afflicted with epilepsy enhanced the animals’ cognitive function and decreased the incidence of seizures. The investigation centered around temporal lobe epilepsy (TLE), the most typical seizure ailment worldwide, impacting approximately 50 million individuals on a global scale.
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Slaying zombies
TLE may manifest subsequent to physical trauma or infection, and less frequently, may stem from genetic predispositions. Nevertheless, the precise connection linking such elements to fits and cognitive decline remains ambiguous.
Simultaneously, a novel notion has surfaced pertaining to the involvement of “zombified” cells in instances of epilepsy.
Whenever cells undergo damage, they frequently initiate programmed cellular demise, instigating self-destruction. Conversely, particular cells may enter a phase termed senescence, wherein they cease to proliferate akin to healthy cells yet persist in their refusal to undergo mortality.
Study co-author Patrick Forcelli, a pharmacologist affiliated with Georgetown University, communicated to Live Science that the influence exerted by such cells has garnered considerable attention among neuroscientists. “There’s been an increasing acknowledgment that cellular senescence may assume a noteworthy function in a spectrum of cerebral ailments,” he articulated.
His research team observed that such senescent cells exhibited behavioral patterns akin to those displayed by brain cells at the inception of a seizure. Both the senescent cells and pre-epileptic cerebral regions give rise to tissue scarring, medically termed fibrosis. In their recent publication, Forcelli and his peers investigated whether the ablation of senescent cells from the brain could potentially modulate the manifestations of TLE.
The research team initiated their investigation by probing for indicators of senescence in brains impacted by TLE. Selected patients diagnosed with TLE undergo surgical removal of specific brain segments to aid in diminishing or eradicating their seizures. The researchers juxtaposed cerebral tissue specimens obtained from such patients with post-mortem samples sourced from individuals devoid of TLE.
Remarkably, the cohort lacking TLE exhibited a significantly advanced age relative to the TLE cohort, as noted by Forcelli. Notwithstanding this disparity, the group afflicted with epilepsy showcased a fivefold surge in the prevalence of senescent cells within their tissue specimens, on average.
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We also shielded a significant proportion of subjects from ever exhibiting seizures, and thus, this represents a disease-modifying strategy in that regard.
Patrick Forcelli, Georgetown University
Subsequently, utilizing mouse models of TLE, the research team validated that the subjects also manifested escalated indications of senescence within their brains compared to mice unaffected by seizures. Such indications of senescence were most notably correlated with microglia, specialized cells constituting a fraction of the brain’s endogenous immune system. Dysfunctional microglia are being increasingly associated with various cerebral disorders, encompassing dementia.
Subsequently, the team endeavored to eliminate senescent cells from the mice. Certain mice were administered a concoction comprising the leukemia medication dasatinib alongside the anti-inflammatory plant-derived pigment quercetin. This unique combination has exhibited repetitive efficacy in prior investigations for diminishing senescent cell counts; such interventions are recognized as senolytics.
James Kirkland, a gerontologist affiliated with Cedars-Sinai Medical Center who initially pinpointed the senolytic properties of the two aforementioned compounds, disclosed to Live Science that they target the signaling pathways exploited by senescent cells to withstand conventional cellular demise.
Dasatinib has secured endorsement as a cancer therapeutic from the U.S. Food and Drug Administration (FDA), whereas quercetin is presently governed as a dietary supplement and food constituent, acknowledged as safe for human consumption. Future trials would be essential to assess the effectiveness of this treatment regimen as a senolytic agent in humans.
A delicate balance
The dual therapeutic approach mitigated several symptoms within the mice. “We demonstrated the capacity to reinstate normative cognitive abilities among the mice” while substantially diminishing their seizures, elucidated Forcelli. “We also shielded a significant proportion of subjects from ever exhibiting seizures, and thus, this represents a disease-modifying strategy in that regard.”
In an independent experiment, Forcelli’s team endeavored to eradicate the entirety of microglia — encompassing both healthy and senescent variants — from the mice afflicted with TLE. This expansive ablation yielded no amelioration for the subjects, attributable, in part, to the resilience of senescent cells against the broad-spectrum therapeutic intervention.
“We eradicated substantial quantities of healthy microglia, whilst preserving the presence of senescent microglia,” Forcelli conveyed. Prior investigations have postulated that microglia fulfill both deleterious and safeguarding roles in the context of epilepsy, he incorporated. The impact of a diminutive subset of senescent cells counteracting a more substantial population of healthy microglia could potentially account for this ambiguity. Moreover, this implies that any therapeutic endeavors directed at microglia would necessitate precise targeting of the senescent variants.
Forcelli intends to undertake additional investigations to discern the optimal temporal window for administering prospective senolytic treatments in the context of TLE. For instance, should the medication be dispensed immediately upon experiencing head trauma, or might its efficacy persist if administered subsequent to a delay of one week or one month?
Furthermore, Kirkland posited that targeting senescence alongside other aging-associated processes could possess applicability across a diverse spectrum of conditions. Nevertheless, he cautioned that the broader populace should defer to the findings of sanctioned clinical assessments as opposed to ingesting commercially obtainable supplements marketed with touted senolytic attributes.
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He remarked that such supplements might encompass constituents unlisted on their respective labels or hazardously augmented concentrations of the active moiety.
“An issue arises concerning quality management given the dearth of regulatory oversight,” Kirkland pronounced. Within the U.S., supplements are exempt from the stringent safety, efficacy, and quality evaluations imposed on pharmaceutical drugs, thus claims regarding their effects on the body remain frequently untested or under-tested.
Happily, thorough clinical assessments are presently probing various classes of senolytic compounds. Kirkland stated that pre-clinical endeavors have discerned approximately “60 or 70” conditions wherein senolytics may impede or forestall disease. “A novel epoch is impending,” he concluded.
Disclaimer
This article is for informational purposes only and is not meant to offer medical advice.
RJ MackenzieLive Science Contributor
RJ Mackenzie is an award-nominated science and health journalist. He has degrees in neuroscience from the University of Edinburgh and the University of Cambridge. He became a writer after deciding that the best way of contributing to science would be from behind a keyboard rather than a lab bench. He has reported on everything from brain-interface technology to shape-shifting materials science, and from the rise of predatory conferencing to the importance of newborn-screening programs. He is a former staff writer of Technology Networks.
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