Caffeine improves memory and cognition via modulating neural progenitor cell survival and decreasing oxidative stress in Alzheimer's rat model.

AIMS: Caffeine possesses potent antioxidant, anti-inflammatory and anti-apoptotic activities against a variety of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The goal of this study was to investigate the protective role of a psychoactive substance like caffeine on hippocampal neurogenesis and memory functions in streptozotocin (STZ)-induced neurodegeneration in rats. BACKGROUND: Caffeine is a natural CNS stimulant, belonging to the methylxanthine class, and is a widely consumed psychoactive substance. It is reported to abate the risk of various abnormalities that are cardiovascular system (CVS) related, cancer related, or due to metabolism dysregulation. Short-term caffeine exposure has been widely evaluated, but its chronic exposure is less explored and pursued. Several studies suggest a devastating role of caffeine in neurodegenerative disorders. However, the protective role of caffeine on neurodegeneration is still unclear. OBJECTIVE: Here, we examined the effects of chronic caffeine administration on hippocampal neurogenesis in intracerebroventricular STZ injection induced memory dysfunction in rats. The chronic effect of caffeine on proliferation and neuronal fate determination of hippocampal neurons was evaluated by co-labeling of neurons by thymidine analogue BrdU that labels new born cells, DCX (a marker for immature neurons) and NeuN that labels mature neurons. METHOD: STZ (1 mg/kg, 2 µl) was injected stereotaxically into the lateral ventricles (intracerebroventricular injection) once on day 1, followed by chronic treatment with caffeine (10 mg/kg, i.p) and donepezil (5 mg/kg, i.p.). Protective effect of caffeine on cognitive impairment and adult hippocampal neurogenesis was evaluated. RESULT: Our findings show decreased oxidative stress burden and amyloid burden following caffeine administration in STZ lesioned SD rats. Further, double immunolabeling with bromodeoxyuridine+/doublecortin+ (BrdU+/DCX+) and bromodeoxyuridine+/ neuronal nuclei+ (BrdU+/NeuN+) has indicated that caffeine improved neuronal stem cell proliferation and long term survival in STZ lesioned rats. CONCLUSION: Our findings support the neurogenic potential of caffeine in STZ induced neurodegeneration.

Cellular studies and sustained drug delivery via nanostructures fabricated on 3D printed porous Neovius lattices of Ti6Al4V ELI.

Site-specific drug delivery has the potential to reduce drug dosage by 3- to 5-folds. Given the propensity of drugs used in the treatment of tuberculosis and cancers, the increased drug dosages via oral ingestion for several months to a few years of medication is often detrimental to the health of patients. In this study, the sustained delivery of drugs with multiscale structured novel Neovius lattices was achieved. 3D Neovius open cell lattices (NOCL) with porosities of 40%, 45%, and 50% were fabricated layer-by-layer on the laser bed fusion process. Micron-sized Ti6Al4V ELI powder was used for 3D printing. The Young's modulus achieved from the novel Neovius lattices were in the range of 1.2-1.6 GPa, which is comparable to human cortical bone and helps to improve implant failure due to the stress shielding effect. To provide sustained drug delivery, nanotubes (NTs) were fabricated on NOCLs via high-voltage anodization. The osteogenic agent icariin was loaded onto the NOCL-NT samples and their release profiles were studied for 7 d. A significantly steady and slow release rate of 0.05% per hour of the drug was achieved using NOCL-NT. In addition, the initial burst release of NOCL-NT was 4 fold lower than that of the open-cell lattices without NTs. Cellular studies using MG63 human osteoblast-like cells were performed to determine their biocompatibility and osteogenesis which were analyzed using Calcein AM staining and Alamar Blue after 1, 5, and 7 d. 3D printed NOCL samples with NTs and with Icariin loaded NTs demonstrated a significant increase in cell proliferation as compared to as printed NOCL samples.

Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease.

Dopamine controls various physiological functions in the brain and periphery by acting on its receptors D1, D2, D3, D4, and D5. Dopamine receptors are G protein-coupled receptors involved in the regulation of motor activity and several neurological disorders such as schizophrenia, bipolar disorder, Parkinson's disease (PD), Alzheimer's disease, and attention-deficit/hyperactivity disorder. Reduction in dopamine content in the nigrostriatal pathway is associated with the development of PD, along with the degeneration of dopaminergic neurons in the substantia nigra region. Dopamine receptors directly regulate neurotransmission of other neurotransmitters, release of cyclic adenosine monophosphate, cell proliferation, and differentiation. Here, we provide an update on recent knowledge about the signalling mechanism, mode of action, and the evidence for the physiological and functional basis of dopamine receptors. We also highlight the pivotal role of these receptors in the modulation of neurogenesis, a possible therapeutic target that might help to slow down the process of neurodegeneration.

Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in neurodegenerative diseases.