Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways.

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations.

Suggesting 7,8-dihydroxyflavone as a promising nutraceutical against CNS disorders.

7,8-dihydroxyflavone (DHF), a naturally-occurring plant-based flavone, is a high-affinity tyrosine kinase receptor B (TrkB) agonist and a bioactive molecule of therapeutic interest for neuronal survival, differentiation, synaptic plasticity and neurogenesis. In the family of neurotrophic factors, this small BDNF-mimetic molecule has attracted considerable attention due to its oral bioavailability and ability to cross the blood-brain barrier. Recent evidences have shed light on the neuroprotective role of this pleiotropic flavone against several neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, Huntington's disease, and other CNS disorders. DHF also elicits potent protective actions against toxins-induced insults to brain and neuronal cells. DHF shows promising anti-oxidant and anti-inflammatory properties in ameliorating the neurodegenerative processes affecting the CNS. This review provides an overview of the significant neuroprotective potentials of DHF and discusses how it exerts its multitudinous beneficial effects by modulating different pathways linked with the pathophysiology of CNS disorders, and thus proposes it to be a nutraceutical against a broad spectrum of neurological disorders.

Lycopene - A pleiotropic neuroprotective nutraceutical: Deciphering its therapeutic potentials in broad spectrum neurological disorders.

Lycopene is a naturally occurring carotenoid found abundantly in red fruits and vegetables. Myriads of literature documented potential health benefits of lycopene, owing to its sublime capacity of suppressing oxidative stress, inflammation, and modulation of various cell survival pathways. Due to its lipophilic nature, lycopene can reach brain adequately by traversing the blood-brain barrier thereby extending it's promising therapeutic benefits in neurological disorders. Lycopene efficiently assists in restoring the characteristic behavioural and pathophysiological changes associated with neurodegenerative disorders, epileptic conditions, aging, subarachnoid hemorrhage, spinal cord injury, and neuropathy. The detrimental impacts of environmental neurotoxins on brain and neuropathological consequences of consumption of high-lipid diet can also be mitigated by lycopene. Apart from its high antioxidant potency, lycopene confers neuroprotection by preventing proteinopathies, neuroinflammation, apoptosis, cerebral edema, and synaptic dysfunction. This review provides a lucid idea on the potential multi-faceted benefits of lycopene in disorders of the central nervous system and elucidates the molecular mechanisms and pathways of its action.

Natural Products and Their Therapeutic Effect on Autism Spectrum Disorder.

Autism is a complex neurodevelopmental disorder that is evident in early childhood and can persist throughout the entire life. The disease is basically characterized by hurdles in social interaction where the individuals demonstrate repetitive and stereotyped interests or patterns of behavior. A wide number of neuroanatomical studies with autistic patients revealed alterations in brain development which lead to diverse cellular and anatomical processes including atypical neurogenesis, neuronal migration, maturation, differentiation, and degeneration. Special education programs, speech and language therapy, have been employed for the amelioration of behavioral deficits in autism. Although commonly prescribed antidepressants, antipsychotics, anticonvulsants, and stimulants have revealed satisfactory responses in autistic individuals, adverse side effects and increased risk of several other complications including obesity, dyslipidemia, diabetes mellitus, thyroid disorders, etc. have compelled the researchers to turn their attention toward herbal remedies. Alternative approaches with natural compounds are on continuous clinical trial to confirm their efficacy and to understand their potential in autism treatment. This chapter aims to cover the major plant-based natural products which hold promising outcomes in the field of reliable therapeutic interventions for autism.

Neuroprotective attributes of L-theanine, a bioactive amino acid of tea, and its potential role in Parkinson's disease therapeutics.

Meta-analyses of tea consumption and reduced risk of Parkinson's disease have thrown light in the pathway of exploring beneficial properties of tea components. On the basis of dry mass, a typical black or green tea beverage contains approximately 6% of free amino acids, which impart high quality, taste and distinctive aroma to the tea infusion. L-theanine (chemically known as γ-glutamylethylamide) is a non-proteinogenic amino acid of tea that takes part in the biosynthesis of its polyphenols. Recently discovered neuroprotective effects of L-theanine can be attributed to its structural analogy with glutamate, the principal excitatory neurotransmitter in brain. This unique amino acid also bears a potential to ameliorate the pathophysiological changes associated with Parkinson's disease as it displays antioxidant and anti-inflammatory properties, improves motor behavioral abnormalities, increases dopamine availability and may cause a favorable downshift in neurodegeneration due to glutamate excitotoxicity. To gain an explicit understanding of the role of L-theanine, this review article is the first one to focus on its mechanism of neuromodulatory action and to critically evaluate the possibilities of employing this bioactive amide in the forage of anti-Parkinsonian medication. We also hypothesize the idea of L-theanine being a potent natural agent against L-DOPA induced dyskinesia, since long-term reliance on dopamine replacement therapy is linked with elevation in glutamate receptor activity.

Garcinol, a multifaceted sword for the treatment of Parkinson's disease.

Garcinol, the principal phytoconstituent of plants belonging to the genus Garcinia, is known for its anti-oxidant as well as anti-inflammatory properties, which can be extended to its possible neuroprotective role. Recent reports disseminate the capacity of garcinol to influence neuronal growth and survival, alter the neurochemical status in brain, as well as regulate memory and cognition. The concomitant neuro-rescue property of garcinol may render it as an effective compound in Parkinson's disease (PD) therapeutics since it is capable of ameliorating the related pathophysiological changes. Emerging pieces of evidence linking histone acetylation defects to the progression of neurodegenerative diseases provide an effective basis for targeting PD. Hyperacetylation of histones has been reported in Parkinsonian brain, which demands the use of pharmacological inhibitors of histone acetyltransferases (HAT). Garcinol serves as a potent natural HAT inhibitor and has unveiled promising results in molecular interaction studies against Monoamine oxidase B (MAO-B) and Catechol-O-Methyltransferase (COMT), as well as in L-DOPA induced dyskinesia. This review highlights the prospective implications of garcinol as a novel anti-Parkinsonian agent, and establishes a bridge between histone acetylation defects and the pathological aspects of PD.

Garcinol, an effective monoamine oxidase-B inhibitor for the treatment of Parkinson's disease.

Loss of dopamine containing neurons in the substantia nigra pars compacta of midbrain, and resultant depletion of dopamine in the striatum is the cause of Parkinson's disease (PD), which is associated with motor abnormalities. Replenishment of dopamine by oral supplementation of its precursor, the levodopa (L-DOPA), remains the primary mode of treatment of PD, despite its potential side-effects after prolonged use in patients. To reduce the daily dosing of L-DOPA in patients, inhibitors of dopamine catabolizing enzymes, particularly monoamine oxidase-B (MAO-B), are prescribed. The most widely used MAO-B inhibitor to maintain the bioavailability of dopamine in the brain of PD patients is L-deprenyl, despite of its potential side-effects. The present study identified Garcinol as a potential candidate in the treatment paradigm of PD by virtue of its exorbitant MAO-B inhibitory potential. The inhibitory potential is comparable to the known MAO-B inhibitors, which was evaluated using molecular docking technique. Owing to its known antioxidant, anti-inflammatory and catechol-o-methyl transferase inhibitory potential, the molecule would confer neuroprotection as well, and thus, the present study is of immense significance in the treatment paradigm of PD.

Attenuation of Aluminum Chloride-Induced Neuroinflammation and Caspase Activation Through the AKT/GSK-3ß Pathway by Hesperidin in Wistar Rats.

Hesperidin, a flavanoglycone abundantly present in citrus fruits, is reported to have antioxidant, anti-inflammatory, and neuroprotective properties. Previous reports from our laboratory indicated the neuroprotective effect of hesperidin against aluminum chloride (AlCl3)-induced memory loss, acetylcholine esterase hyperactivity, oxidative stress, and enhanced expression of amyloid ß protein biosynthesis-related markers. However, their role on AlCl3-induced inflammation, caspase activation, Tau pathology, altered Akt/GSK 3ß signaling pathway, and Aß clearance marker has not yet been fully elucidated. Intraperitonial injection of AlCl3 (100 mg/kg body weight) for 60 days significantly elevated the expressions of insulin-degrading enzyme (IDE), cyclin-dependent kinase 5 (CDK 5), and phosphoTau (pTau); inflammatory markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), NF-kB, cyclooxygenase-2 (COX-2), interleukin (IL)-1ß, IL-4, IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS); and apoptotic markers including cytosolic cytochrome c (cyto c), caspase-3, caspase-8, and caspase-9, and lowered expressions of mitochondrial cyto c, phospho-Akt (pAkt) and phospho-glycogen synthase kinase-3ß (pGSK-3ß) in the hippocampus and cortex. Co-administration of hesperidin to AlCl3 rats for 60 days significantly ameliorated the aluminum-induced pathological changes. The behavioral studies also supported the above findings. Our results imply that treatment with hesperidin might be a potent option for treating the symptoms of cognitive impairment in Alzheimer's disease by targeting its most prominent hallmarks.

Neuroprotective potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action.

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as ß-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.