9. Conclusion

Moreover, FSK-mediated cAMP/PKA/CREB activation were found to inhibit LPS- and cytokine-mediated production of NO as well as the expression of iNOS, whereas compounds (H-89 and (Rp)-cAMP) that decrease PKA activity stimulated the production of NO and the

The brain is strongly dependent on the ATP production of the cell energy-producing organelle, the mitochondrion. There is a large body of evidence involving mitochondrial dysfunctions in ASD. Palmieri and Persico, regarding ASD, oxidative phosphorylation (OXPHOS) in the mitochondrion requires at least 80 proteins, of which only 13 are encoded by the mtDNA, while mitochondrial functioning has been estimated to need the participation of approximately 1500 nuclear genes. Mitochondrial dysfunction is present in the brains of individuals with ASD and may play a role in its core cognitive and behavioral symptoms. Alternatively, mitochondria can be damaged by endogenous stressors associated with ASD such as elevated pro-inflammatory cytokines resulting from an activated immune system or other conditions associated with oxidative stress. Oxidative stress may be a key link between mitochondrial dysfunction and ASD as reactive oxygen species (ROS) generated from pro-oxidant environmental toxicants and activated immune cells can result in mitochondrial dysfunction. Excess production of free radicals or impaired antioxidant mechanisms may cause oxidative stress: impaired mitochondrial function then leads to further oxidative stress and a vicious negative cycle can ensue. Instead, abnormal functioning appears secondary to excessive Ca2+ levels. Mitochondrial dysfunctioning caused depletion of ATP, that further decrease the level of cAMP. Forskolin, increase in intracellular cAMP, through the phosphorylation of CREB which perform neuroprotective functioning associate with mitochondrial dysfunctioning [69].

Autistic brain which may reflect enhanced cortical plasticity which is defined as the process of microstructural construction of synapses occurring during development and the remodeling of these synapses during learning [70]. Enhanced synaptic plasticity triggers a regional reorganization of brain functions that account for both the unique aspects of autism and its variability [71]. Activation of cAMP/PKA has been mainly implicated in stimulating learning and mem-

Summarizing the whole information given above, FSK confirmed a versatile role in autism where it activates the AC/cAMP-mediated PKA/CREB activation. Moreover, on other side FSK act as a co-activator in brain that follows the GS pathway through the activation of D1 receptor. There is least availability of selective AC activation and so far only limited reports suggest

expression of iNOS in rat primary astrocytes [68].

16 Recent Advances in Neurodegeneration

8.4. Forskolin against cognitive dysfunction

ory. FSK activate cAMP/CREB in hippocampal region [72].

8.5. Possible involvement of FSK in PPA-induced autism

beneficial effect of FSK in neurodegeneration animal model.

8.3. Forskolin against mitochondrial dysfunctioning

In conclusion, the current study strongly confirms that the administration of propionic acid induces brain lesions that are similar to the behavioral, histological, morphological, biochemical, neurochemical, and pathological features of autism. After Chronic administration of propionic acid in the rats as proven by motor dysfunctions, biochemical and neurochemical alternations. The literature finding in the current study reveals that adenylyl cyclase activator, that is, FSKmediated cAMP/CREB activation, might be a unique platform for the prevention of neurodegenerative diseases. Thus in conclusion, neuroprotective and neuro restoration effects of FSK may be due to favorable modulation of CREB-mediated signaling. The involvement of cAMP/PKA/CREB pathway, anti-oxidant, anti-inflammatory and neuroprotective effect of test drug FSK may be the possible mechanisms at least in part underlying the observed effects (Figure 4).

Furthermore, with cAMP/PKA/CREB signaling in regulation of neuronal functioning, the future studies can be designed to investigate the protective and therapeutic potency of forskolin in animal models of brain hemorrhage, Huntington's disease and Parkinson's disease and to find out if cAMP-mediated CREB pathway is equally implicated in the disease pathogenesis or progression. So, now we can finally conclude the significant mitochondrial restorative effects of the FSK may be due to showing its improved motor and cognitive functions as well as to restore the energy levels and antioxidant and anti-inflammatory defense system.
