Elsevier

Experimental Gerontology

Volume 138, September 2020, 111006
Experimental Gerontology

Fisetin prevents the aging-associated decline in relative spectral power of α, β and linked MUA in the cortex and behavioral alterations

https://doi.org/10.1016/j.exger.2020.111006Get rights and content

Highlights

  • Current in vivo study investigates the antiaging potential of fisetin electrophysiologically.

  • Fisetin improved the relative spectral power of α(8–12 Hz), β(12–28 Hz), and MUA count in aged animals.

  • Fisetin decreased the age-associated learning and memory deficit in MWM task.

  • Open-field activity parameters confirmed the decrease in anxiety level in fisetin supplemented aged rats.

Abstract

Mental health in old age is of great concern due to the increased incidence of neurological and psychiatric diseases. With age, probability of cognitive and behavioral deficits increase and the prognosis deteriorates. Although a few in vitro studies have reported that flavonoid fisetin is beneficial for healthy aging, its effect on deteriorating mental health with aging in vivo is very limited and poorly understood. The brain aging is physiologically characterized by electroencephalograph (EEG) wave frequency, power, and distribution. Brain oscillatory waves from neural tissue get altered by various sensory-cognitive inputs. Besides, the fast-wave α(8–12 Hz)- and β(12–28 Hz)-oscillations are associated with coordination and indeed deal with complex behavioral performances. Therefore, the effect of fisetin supplementation on age-associated EEG mean cortical spectral power in α- and β-oscillations, multi-unit activity (MUA) count were studied in vivo which was not addressed so far. Besides, age-associated cognitive and behavioral alterations were also studied.

The relative spectral power of α and β declined along with the MUA count in aged rats compared to young. However, supplementing fisetin for four weeks has improved relative α-power, β-power, and MUA count in aged rats. Also, fisetin supplemented aged rats showed significantly improved cognitive and behavioral performances than aged controls.

These findings demonstrated the relative cortical spectral power in α-, β-oscillations, and MUA count change in aged rats and that some of these changes and behavioral alterations may be partly as a result of oxidative stress, which was prevented significantly in fisetin supplemented aged rats. Thus, fisetin boosted mental health in the aged animals.

Introduction

Aging is an inevitable physiological process associated with deteriorating healthy brain functions. Minimizing the negative effects and maintaining the normal brain functions are the key concerns to improve the quality of life while aging. The proper functioning of the brain depends on the underlying neurons that are part of neuronal networks and plasticity. The elderly population is more prone to changes in neuronal structure, fluctuating electrical signaling (Coskren et al., 2015), disturbed sensory-motor activity (Bernard and Seidler, 2014), and impaired cognitive functions (Hernandez et al., 2018; Sousa et al., 2018) which eventually affect the normal functioning of the brain than the younger.

The electrophysiological aspect of brain aging is indexed by neuronal excitability. The fluctuations between neuronal excitation and inhibition induce different firing patterns (Joshua et al., 2007; Haegens et al., 2011). The spatiotemporal inputs from thousands of neurons to a specific neural assembly result in regular fluctuations referred to as neural brain oscillations (Hanslmayr et al., 2012). Studies on brain oscillatory activities are essential for the understanding of neuronal electrical communication (Anderson and Taraschenko, 2018). Few intracranial EEG and magneto-encephalogram studies have reported the alterations in brain oscillatory activities play a crucial role in long-term memories (Düzel et al., 2010; Fell and Axmacher, 2011). Cortical EEG is the most studied form of intrinsic brain electrical activity that reflects synaptic field potentials of the cortex (Kutas and Dale, 1997).

Age-associated changes in the neurotransmission affect the neuronal response and temporal processing that lead to disruption of neuronal network plasticity and oscillations in the cortical and subcortical areas (Caspary et al., 2008; Alitto and Yang, 2010). These neural brain oscillations can be measured typically at different frequencies such as fast-wave α(8-12 Hz) and β(12-28 Hz) oscillations observed in normal awake EEG recordings (Schutter and Knyazev, 2012). The sensorimotor α-oscillations originate from the somatosensory cortex, whereas sensorimotor β-oscillations from the motor cortex (Hari and Salmelin, 1997). The sensorimotor α-oscillations are linked with the excitability of the somatosensory cortex in rodents (Aleksander et al., 2011) and a marked reduction in α-oscillations was observed in the resting state (Ryouhei et al., 2017). Similarly, β-oscillations are linked with sensory and information processing and motor functions (Klimesch, 1996; Pavlidou et al., 2014).

Significant anatomical, cellular and molecular alterations are observed in the aging brain and the contributing key factor for these alterations is oxidative stress (Thakur et al., 2012). Several natural compounds like flavonoids and antioxidant extracts are reported effective against aging and age-associated neurological disorders (Leandro Cattelan et al., 2015; Hong Ru et al., 2009).

Flavonoid fisetin (3, 3′, 4′, 7 –tetrahydroxyflavone) is a secondary metabolite produced in many plants, exist in their fruits, barks, hardwood (Hostetler et al., 2017; Wang et al., 2018). Fisetin is present in strawberries, onions, persimmons, apples, grapes, kiwi, etc. (Grynkiewicz and Demchuk, 2019). Recently, several biological activities of fisetin are identified, that includes neuroprotective, anti-inflammatory, and antioxidative effects to name a few (Pamela et al., 2011; Mansuri et al., 2014).

Fisetin modulates various pathways involved in aging (Maher, 2009), improves ionic homeostasis in aged rats (Sandeep et al., 2019), and protects against cytotoxicity in neuron-like PC12 cells (Jui-Hung et al., 2017). Fisetin is also reported to be a senotherapeutic that extends health and longevity in mice model of the progeroid syndrome (Yousefzadeh et al., 2018). Fisetin has reduced the impact of aging as confirmed from the behavioral and physiological in vitro study on fisetin fed SAMP8 mice (Antonio et al., 2018). A few other in vitro studies have deduced how fisetin influences the cellular pathways in aging (Syed et al., 2013; Pallauf et al., 2017). However, in vivo studies on the cortical spectral power of α, β, and MUA count in brain aging following fisetin supplementation have not been reported. As the fast-waves (α and β) are involved in complex behavioral activities, we also studied the linked cognitive and behavioral activities.

In the present study, we recorded the EEG (for spectral power analysis of α and β) and MUA in young and aged rats with and without fisetin supplementation, to enhance our understanding of age-associated post-synaptic and action potential changes in the brain electrical activity as well as cognitive and behavioral activity in response to fisetin.

Section snippets

Materials

Fisetin was purchased from Sigma Aldrich Chemical Company, USA. Tissue compatible stainless-steel electrodes and wires used in the stereotaxic surgery and electrophysiological recordings were obtained from Plastic One, Roanoke, VA, USA.

Animals

Male Wistar rats (n = 20) were obtained from the Central Laboratory Animal Resources, JNU, New Delhi, India for this study. All the rats were housed in pairs in standard laboratory cages (12″ × 9″ × 6″) in a well-ventilated room, maintained at 23 ± 2 °C and

Electrophysiological changes with aging and in response to fisetin supplementation

The representative stretch of EEG and MUA from the frontal cortex of conscious unrestrained awake (passive or quiet wakefulness) rats shown in Fig. 2.

Discussion

Several electrophysiological studies have reported that some brain electrical alterations are age-dependent (Coskren et al., 2015; Mateusz et al., 2012). The current in vivo study investigated the aging-associated brain electrical alterations in the cortical EEG spectral power (α- and β-oscillations) and the multi-unit activity count in young and aged animals, in response to fisetin supplementation. Fisetin supplemented aged rats showed an improvement in these electrical parameters of the brain

Conclusion

In conclusion, this study suggests fisetin supplementation has improved the relative α-power, β-power, and linked MUA in aged rats suggesting fisetin's beneficial effect on aging-associated electrical alterations, thus boosting mental health in the aged. Fisetin not only improved the electrophysiological functions of the brain but also improved the cognitive and behavioral performances by modulating the spectral α-, β-power, and the MUA count. This in vivo study has strengthened the antiaging

Author statement

Conceptualization and design of study: Deepak Sharma, Rameshwar Singh, Jharana Das Acquisition of data: Jharana Das, Stanzin Ladol Analysis and/or interpretation of data: Jharana Das, Sasmita Kumari Nayak, Stanzin Ladol, Drafting the manuscript: Jharana Das, Sasmita Kumari Nayak, Revising the manuscript critically: Jharana Das, Rameshwar Singh, Deepak Sharma, Reviewing and Editing: Jharana Das, Stanzin Ladol, Sasmita Kumari Nayak.

Declaration of competing interest

None.

Acknowledgment

The authors acknowledge financial support by the Department of Biotechnology (BT/PR4993/MED/30/914/2012), New Delhi, India, and the Indian Council of Medical Research (3/1/2/93/Neuro/2018-NCD-I), New Delhi for this work.

References (68)

  • Wolfgang Klimesch

    EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis

    Brain Res. Rev.

    (1999)
  • R. Lalonde et al.

    The relation between open-field and emergence tests in a hyperactive mouse model

    Neuropharmacology

    (2009)
  • Ksenia Z. Meyza

    Age increases anxiety and reactivity of the fear/anxiety circuit in Lewis rats

    Behav. Brain Res.

    (2011)
  • Richard Morris

    Developments of a water-maze procedure for studying spatial learning in the rat

    J. Neurosci. Methods

    (1984)
  • Hiroshi Ohkawa et al.

    Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction

    Anal. Biochem.

    (1979)
  • Ronald S. Petralia et al.

    Communication breakdown: the impact of ageing on synapse structure

    Ageing Res. Rev.

    (2014)
  • Tian-yang Wang et al.

    Bioactive flavonoids in medicinal plants: structure, activity and biological fate

    Asian Journal of Pharmaceutical Sciences

    (2018)
  • Matthew J. Yousefzadeh

    Fisetin is a senotherapeutic that extends health and lifespan

    EBioMedicine

    (2018)
  • Sobolewski Aleksander

    The 5–12 Hz oscillations in the barrel cortex of awake rats–sustained attention during behavioral idling?

    Clin. Neurophysiol.

    (2011)
  • David E. Anderson et al.

    Age-related cognitive impairment in humans

  • Currais Antonio

    Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse

    The Journals of Gerontology: Series A

    (2018)
  • Hiroyuki Arakawa

    The effects of isolation rearing on open-field behavior in male rats depends on developmental stages

    Developmental Psychobiology: The Journal of the International Society for Developmental Psychobiology

    (2003)
  • Rony Azouz et al.

    Cellular mechanisms contributing to response variability of cortical neurons in vivo

    J. Neurosci.

    (1999)
  • Samuel P. Burns et al.

    Comparisons of the dynamics of local field potential and multiunit activity signals in macaque visual cortex

    J. Neurosci.

    (2010)
  • Cristina Carvalho et al.

    Oxidative stress: a major player in cerebrovascular alterations associated to neurodegenerative events

    Front. Physiol.

    (2018)
  • Donald M. Caspary

    Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system

    J. Exp. Biol.

    (2008)
  • Patrick J. Coskren

    Functional consequences of age-related morphologic changes to pyramidal neurons of the rhesus monkey prefrontal cortex

    J. Comput. Neurosci.

    (2015)
  • Jharana Das et al.

    Antiepileptic effect of fisetin in iron-induced experimental model of traumatic epilepsy in rats in the light of electrophysiological, biochemical, and behavioral observations

    Nutr. Neurosci.

    (2017)
  • Juergen Fell et al.

    The role of phase synchronization in memory processes

    Nat. Rev. Neurosci.

    (2011)
  • Simon P. Fisher

    Stereotypic wheel running decreases cortical activity in mice

    Nat. Commun.

    (2016)
  • Borghini Giulia

    Alpha oscillations are causally linked to inhibitory abilities in ageing

    J. Neurosci.

    (2018)
  • Rabiller Gratianne

    Perturbation of brain oscillations after ischemic stroke: a potential biomarker for post-stroke function and therapy

    Int. J. Mol. Sci.

    (2015)
  • Grzegorz Grynkiewicz et al.

    New perspectives for fisetin

    Frontiers in Chemistry

    (2019)
  • Gilles J. Guillemin

    Dietary supplements/antioxidants: impact on redox status in brain diseases

    Oxidative Med. Cell. Longev.

    (2017)
  • View full text